Block 2 presentation 1 - Cell Bio Transduction part 1

Question 1

Signal transduction:

Answer 1

Signal transduction is Detection of specific signals at the cell surface and the mechanism by which such signals are transmitted into the cell’s interior, resulting in changes in cell behavior and/or gene expression

Question 2

The different type of chemical signals that can be received by a cell

Answer 2

Different types of chemical signals can be received by cells

Ligand: substance that binds to a specific receptor, thereby initiating the particular event or series of events for which that receptor is responsible

Primary messenger: A molecule that binds to a receptor, thereby beginning the process of transmitting a signal to the cell. they have a short half life.

Second messenger: any of several substances, including cyclic AMP, calcium ions, inositol triphosphate, and diacylglycerol, that transmit signals from extracellular signaling ligands to the cell interior

Question 3

Types of Chemical Messengers

Answer 3

Types of Chemical Messengers

Amino acids or their derivatives, Peptides, Proteins, Fatty acids, Nucleosides or nucleotides, Steroid hormones, Retinoids, eicosanoids

Question 4

Extracellular Signal Molecules Can Act Over what distances? explain.

Answer 4

Extracellular Signal Molecules Can Act Over Either Short or Long Distances

Endocrines:
Each endocrine hormone is secreted by a specific cell type, enters the blood, and exerts its actions on specific target cells, which may be some distance away.

Paracrines:

• Paracrine actions are those performed on nearby cells, and the location of the cells plays a role in the specificity of the response
• Very important in limiting immune response to a specific location in the body

Autocrines:
Autocrine actions involve a messenger that acts on the cell from which it is secreted, or on nearby cells that are the same type as the secreting cells.

Question 5

Endocrine Signaling

Answer 5

Endocrine cells secrete hormones into the blood, and these act only on those target cells that carry the appropriate receptors: the receptors bind the specific hormone, which the target cells thereby ”pull” from the extracellular fluid

Question 6

At what speed do extracellular signals move?

Answer 6

Extracellular signals can act slowly or rapidly to change the behavior of a target cell

• Certain types of signaled responses, such as increased cell growth and division, involve changes in gene expression and the synthesis of new proteins; they therefore occur slowly, often starting after an hour or more
• Other responses-such as changes in cell movement, secretion, or metabolism – need not involve changes in gene transcription and therefore occur much more quickly, often starting in seconds or minutes; they may involve the rapid phosphorylation of effector proteins in the cytoplasm

Question 7

Signal transduction pathways can amplify the cellular response to?

Answer 7

Signal transduction pathways can amplify the cellular response to an external signal

Question 8

Different types of cells usually respond differently to the same extracellular signal molecule

Answer 8

A cell’s response to extracellular signals depend not only on the receptor proteins it possesses but also on intracellular machinery by which it integrates and interprets the signal it receives

Additional information (not required)

Example neurotransmitter acetycholine:

Different cell types are specialized to respond to acetylcholine in different ways.

• In some cases (B & C), the receptors for acetylcholine differ.
• In other cases (B & D), acetylcholine binds to similar receptor proteins, but the intracellular signals produced are interpreted differently in cells specialized for different functions.

Question 9

The fate of some developing cells depends on?

Answer 9

The fate of some developing cells depend on their position in morphogen gradients

additional info (not required)

The same molecule acting on the same cell type can have qualitatively different effects depending on the signal’s concentration. This phenomenon is extremely important during development

A morphogen is an extracellular signal molecule which diffuses out from a localized cellular source, generating a signal concentration gradient to which the cells response will be dependent upon.

Example shown here: The different concentrations of morphogen induces expression of different sets of genes, resulting in different cell fates.

Question 10

Each cell is programmed to respond to?

Answer 10

Each cell is programmed to respond to specific combination of extracellular signal molecules

additional info (not required)

Each cell displays a set of receptors that enables it to respond to a corresponding set of signal molecules produced by other cells.

These signal molecules work in combinations to regulate the behavior of the cell.
As shown here,

• an individual cell often requires multiple signals to survive (blue arrows)
• and additional signals to grow and divide (red arrows) or
• differentiate (green arrows).

If deprived of appropriate survival signals, a cell will undergo a form of cell suicide known as apoptosis.

Question 11

Mechanisms in which target cells can become desensitized to an extracellular signal molecule

Answer 11

Mechanisms in which target cells can become desensitized to an extracellular signal molecule include:

• By hiding away the receptor until it’s needed again ( in the recycling endosome). ex insulin signaling
• By destroying the receptor (get sorted in the early endosome and get sent to the late endosome and goes to the lysosome to get degraded.
• shutting off the pathway by various ways like negative feedback loop

• Cell can adjust their sensitivity to a signal
• In responding to many types of stimuli, cells and organisms are able to detect the same percentage of change in a signal over a wide range of stimulus strengths.
• This is accomplished through a reversible process of adaptation or desensitization, whereby a prolonged exposure to a stimulus decreases the cells’ response to that level of stimulus

Question 12

Explain The binding of extracellular signal molecules to either cell-surface or intracellular receptors

Answer 12

The binding of extracellular signal molecules to either cell-surface or intracellular receptors

Most signal molecules are hydrophilic and are therefore unable to cross the target cell’s plasma membrane directly; instead, they bind to cell-surface receptors, which in turn generate signal inside the target cell

Some small signal molecules, by contrast, diffuse across the plasma membrane and bind to receptor proteins inside the target cell- either in the cytosol or in the nucleus.

• Many of these small signal molecules are hydrophobic and nearly insoluble in aqueous solutions; they are therefore transported in the bloodstream and other extracellular fluids bound to carrier proteins, from which they dissociate before entering the target cell.

Question 13

Steroid Receptor Signaling

Answer 13

Steroid Receptor Signaling

There are now two known signaling mechanisms for steroid hormones

1) Nuclear-initiated steroid signaling (Classical signaling)
* Slower, involves changes in gene expression
2) Membrane-initiated steroid signaling
* Faster, includes activation of G proteins and stimulation of protein kinases

Question 14

Steroid hormones are synthesized by?

favorite it!

Answer 14

Type l receptor

Steroid hormones are synthesized from cholesterol:

• Testosterone, estrogen, and progesterone are the sex steroids, produced by the gonads.

Corticosteroids from the adrenal gland:

• Glucocorticoids—stimulate production of glucose
• Mineralocorticoids—act on the kidney to regulate salt and water balance.

type ll receptors

vitamin A receptor

vitamin D receptor

retinoid

thyroid hormone receptor

Steroid hormone receptors have three domains:

DNA Binding Domain
Hormone Binding Domain
Gene Regulatory Domain

mnemonics:

Test Everyone Please (damn UMHS whores): Testosterone, estrogen and progesterone.

Got adrenal problems? Get a GLUC and a MK and there wont be a problem! : Adrenal gland: get Glucocoricoids for glucose and Mineralocorticoids for Kidneys.

Question 15

Thyroid hormone is synthesized from?

Answer 15

Thyroid hormone is synthesized from tyrosine in the thyroid gland.

it is important in development and metabolism. It is transported across the membrane by a carrier protein.

Question 16

What function does vitamin D3 have?

Answer 16

Vitamin D3 regulates Ca2+ metabolism and bone growth.

Question 17

Retinoic acid and related compounds (retinoids) are synthesized from?

Answer 17

Retinoic acid and related compounds (retinoids) synthesized from vitamin A play important roles in vertebrate development

Question 18

Aldosterone

Answer 18

aldosterone a steroid hormone

stimulates renal reabsorption

Question 19

Cortisol

Answer 19

Cortisol a steroid hormone

• Cortisol increases blood sugar through gluconeogenesis
• anti-inflammatory action
• protein breakdown in muscle

Question 20

Estrogens

Answer 20

Estrogens is a steroid protein

• Estrogens controls menstrual cycles
• Estrogens promote development of female secondary sex characteristics

Question 21

What is Progesterone?

Answer 21

Progesterone is a steroid protein

Progesterone causes secretory phase of uterus and mammary glands.

Progesterone causes implantation and maturation of fertilized ovum.

Question 22

testosterone

Answer 22

testosterone is a steroid protein

• testosterone stimulates spermatogenesis
• testosterone promotes developement of male secondary sex characteristics
• testosterone promotes anabolism (The phase of metabolism in which simple substances are synthesized into the complex materials of living tissue.)
• testosterone promotes masculinization of the fetus

Question 23

Nuclear-Initiated Steroid Signaling

(favorite it!)

Answer 23

The lipophilic hormones use intracellular gene-specific trancription factors

• Includes steroid hormones, thyroid hormones, retinoic acid and vitamin D
• Receptors are transcription factors
  
  • They bind to DNA promoter elements in genes and alter gene expression
  • Steroid hormone receptors often have Zinc finger DNA binding domains

The hormones need to be transported in the blood bound to carrier proteins such as serum albumin, steroid hormone-binding protein or thyroid hormone-binding globulin

Some receptors primarily reside in the nucleus,

Others, such as glucocorticoid receptor are found in the cytosol until the steroid interacts with it

Question 24

What are the 3 domains seroid receptors?

(favorite it!)

Answer 24

Steroid hormone receptors have three domains:

1. Zinc finger DNA Binding Domain
2. Hormone Binding Domain
3. Gene Regulatory Domain

Question 25

Nuclear-Initiated Steroid Signaling (favorite it!)

Answer 25

Nuclear-Initiated Steroid Signaling * Receptors for these molecules are members of the nuclear receptor superfamily. * They are transcription factors that have domains for ligand binding, DNA binding, and transcriptional activation. * Ligand binding regulates their function as activators or repressors of genes. * Ligand binding has different effects on different receptors. * Some nuclear receptors are inactive in the absence of hormone: Glucocorticoid * Hormone binding may alter the activity of the receptor: Thyroid hormone

Question 26

Glucocorticoid action (favorite it!)

Answer 26

Glucocorticoid action * Inactive Glucocorticoid receptor resides in the cytosol until it binds it’s ligand * Glucocorticoid receptor is bound to **Hsp90 chaperones** in the **absence** of hormone. * Glucocorticoid binding displaces Hsp90 and leads to binding of regulatory DNA sequences.

Question 27

Gene regulation by the thyroid hormone receptor (favorite it!)

Answer 27

Gene regulation by the **thyroid hormone** receptor * In the **absence of hormone**, thyroid hormone receptor is associated with a **corepressor(HDAC)** complex and **represses** transcription of target genes. HAT cannot bind because of this, so there are not acetyl groups to aid in transcription. * **Receptor remains in the nucleus whether or not it is bound to ligand** * Hormone binding results in activation of transcription. At this point, when the hormones bind to the thyroid hormone receptor, HDAC is released and HAT can now bind with it's acetyl groups for transcription to occur. **So thyroid hormone receptors regulate transription whether or not it bind's to its hormone!**

Question 28

Inhibitors of steroid hormone synthesis as cancer therapy (Favorite it!!!!!!!)

Answer 28

* Aromatase inhibitors are used in treatment of estrogen-responsive breast cancer in **_postmenopausal_** women * Examples: ANASTROZOLE and EXEMESTANE * Estrogen is primarily derived from adrenal-produced androgens by the action of the enzyme aromatase in postmenopausal women. * Inhibitors of aromatase can reduce estrogen levels significantly and remove the main source of growth stimulation from estrogen-responsive tumors * Arrest of tumor growth and/or initiation of apoptosis of estrogen-responsive breast tumors occur as a result of treatment with aromatase inhibitors **In mose cases, these drugs are used for blocking the production of the steroid. why? because certain cancers depend on steroid hormone signaling. when they don't have this signaling, they do not grow as rapidly.**

Question 29

Hormone Receptor Antagonists as Cancer Therapies Favorite it!

Answer 29

Hormone Receptor Antagonists as Cancer Therapies * **Receptor** antagonists bind to the hormone receptor and prevent binding of the natural hormone to its receptor. * Selective estrogen receptor modulators such as tamoxifen are important therapies for treatment and prevention of breast cancer. * Tamoxifen works by blocking estrogen receptors in breast, thereby inhibiting estrogen-dependent growth of tumors. * Tamoxifen is used in premenopasaul women with estrogen-receptor positive breast cancer. blocks estrogen by keeping it from binding to the receptor.

Question 30

Tamoxifen and Aromatase Inhibitors

Answer 30

Tamoxifen and Aromatase Inhibitors ## Footnote Oestradiol binds to the oestrogen receptor (ER), leading to dimerization, conformational change and binding to oestrogen response elements (EREs) upstream of oestrogen-responsive genes including those responsible for proliferation. Tamoxifen competes with oestradiol for ER binding whereas aromatase inhibitors reduce the synthesis of oestrogens from their androgenic precursors.

Question 31

Membrane-Initiated Steroid Signaling

Answer 31

Membrane-Initiated Steroid Signaling * Rapid effects of steroid hormones that occur within seconds to minutes after exposure of target cells to steroid hormones are now believed to result from actions of steroid receptors localized to the plasma membrane * Convergence between membrane-initiated steroid signaling and nuclear-initiated steroid signaling permits an overall biological response to the steroid hormone

Question 32

Membrane Steroid Receptors

Answer 32

Membrane Steroid Receptors * Localize to membrane caveolae * Found either facing the outer surface of the plasma membrane or facing the cytosolic side tethered to a scaffolding protein * Activated receptors bound by their specific steroid hormone then associates with a complex of signaling proteins that can include G proteins, growth factor receptors, Src, Ras and other targets.

Question 33

Membrane Steroid Receptors

Answer 33

Membrane Steroid Receptors ## Footnote A | Three classes of membrane receptor are shown illustrating the classic nuclear steroid-hormone receptor associated with a caveola. Aa | The receptor is technically outside the cell and is associated with the outer surface of the plasma membrane in the flask of the caveola. Ab | The receptor is tethered by a scaffolding protein to the plasma membrane on the inner surface of a caveola. Ac | The receptor is tethered to the caveolae by a palmitic acid molecule that is esterified to a receptor Ser or Thr with the fatty-acid side chain 'inserted' into the membrane (palmitoylation). B | A G-protein-coupled receptor with its ligand-binding domain on the outside of the cell and a seven-membrane spanning peptide transition followed by an intracellular peptide domain that can bind G, and proteins. C | A single-spanning membrane receptor with intrinsic kinase activity that might be functional as a monomer. D | Same as C except a homodimer. Caveolae are flask-shaped membrane invaginations present in the outer cell membrane of many cells; they are believed to serve as a 'platform' to accumulate or 'dock' signal-transduction-related molecules.The signal-transduction systems are listed as candidates for mediating rapid responses to steroid hormones and are based on published data93, 94, 95, 96, 97, 98. The details remain to be defined on the basis of careful experimentation. The two ovals with Ras-GTP and c-Raf 'touching' are to suggest that c-Raf was recruited to the complex. AC, adenylyl cyclase; DAG, diacylglycerol; EGFR, epidermal growth factor receptor; e-NOS, endothelial nitric oxide synthase; IP3, inositol triphosphate; MAP, mitogen-activated protein; PI3K, phosphatidylinositol 3-kinase; PIP3, phosphatidylinositol triphosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C.

Question 34

The three largest classes of cell-surface receptor proteins:

Answer 34

The three largest classes of cell-surface receptor proteins: * Ion-channeled coupled receptors * Involved in rapid synaptic signaling between nerve cells and other electrically excitable target cells such as muscle cells. * Mediated by neurotransmitters that transiently open or close and ion channel formed by the protein to which they bind * G-protein-coupled receptors * (also called Heptahelical receptors) * Act by indirectly regulating the activity of a separate plasma-membrane-bound target protein, which is generally either an enzyme or an ion channel * A trimeric GTP-binding protein mediates the interaction between the activated receptor and this target protein * Enzyme-coupled receptors * Either function directly as enzymes or associate directly with enzymes that they activate * **Examples** * Tyrosine kinase receptors * Serine/threonine kinase receptors

Question 35

Ion-channel-receptors

Answer 35

Ion-channeled coupled receptors Involved in rapid synaptic signaling between nerve cells and other electrically excitable target cells such as muscle cells. Mediated by neurotransmitters that transiently open or close and ion channel formed by the protein to which they bind

Question 36

G-Protein-Linked Receptors(Heptahelical Receptors)

Answer 36

G-Protein-Linked Receptors (Heptahelical Receptors) Seven-membrane spanning receptors act via G proteins (**guanine-nucleotide** binding protein) * Ligand binds receptor * Receptors activate G-proteins * G-protein binds target protein and modulates it The structure of G protein-linked receptors * N-terminus: extracellular * C-terminus: cytosolic * G-protein interacts at cytosolic loop between 5th and 6th TM helices **G-protein has 7 transmembrain domain** how you see, what you can smell, how you react to glucogon and norpinephrin is based on this receptor. All types of chemicals bind to Heptahelical Receptors (G protein-linked receptors)

Question 37

The structure and activation of G proteins

Answer 37

Two classes of G proteins: -Large heterotrimeric G proteins * Mediates signal transduction through G protein-linked receptors * Subunits: * G alpha * Binds GTP * G beta and G gama * There are different types of G proteins, some are stimulators (Gs) and others act as inhibitors (Gi) * When ligand interacts with receptors, this causes G alpha to exchange GDP for GTP and dissociate from Gb and Gg * G beta and G gama -Small monomeric GTPase proteins Example: Ras

Question 38

4 major families of trimeric G protein

Question 39

Diversity of G Protein-Coupled Receptor Signal Transduction Pathways

Answer 39

Diversity of G Protein-Coupled Receptor Signal Transduction Pathways Depending on its isoform, the GTP-alpha subunit complex mediates intracellular signaling either indirectly by acting on effector molecules such as adenylyl cyclase (AC) or phospholipase C (PLC), or directly by regulating ion channel or kinase function.

Question 40

Cyclic AMP is a second messenger regulated by some classes of G proteins

Answer 40

Cyclic AMP is a second messenger regulated by some classes of G proteins * **Adenylyl cyclase** (found associated with plasma membrane) forms cyclic AMP (cAMP) from cytosolic ATP * **Gs** signaling pathway activates adenylyl cyclase * **Phosphodiesterase** degrades cAMP

Question 41

Methylxanthines Favorite it!

Answer 41

* Methylxanthines: * caffeine from coffee and tea * theophylline from tea * theobromine from chocolate * Two modes of action: * The principal mode of action of **caffeine is as an antagonist of adenosine receptors (functions as an inhibitor).** * The caffeine molecule is structurally similar to adenosine * **Methylxanthines are also cAMP phosphodiesterase inhibitors**

Question 42

Main intracellular targets of cAMP

Answer 42

* cAMP-dependent kinase or **protein kinase A** (PKA) * PKA is a serine/threonine kinase * PKA has **two regulatory** subunits and **two catalytic** subunits. _When cAMP binds to PKA,_ the regulatory subunits disassociates from catalytic subunits * The cAMP pathways are important for regulating glycogen metabolism, heart contraction, blood clotting and secretion of salts and water in the gut * EPAC (Exchange Protein Activated by Cyclic AMP) * Epac proteins are activated by binding of cAMP and acts as guanine nucleotide exchange factors for Rap GTPases. * They are important in the regulation of cell adhesion, cell proliferation, anti-inflammatory response and in insulin secretion * Ion Channels

Question 43

Gs signaling **Favorite it!**

Answer 43

Gs Signaling 1. Ligand binds to the heptahelical receptor 2. Associated hetrotrimeric Gs protein complex becomes active (alpha subunit binds GTP and dissociates) 3. The alpha-subunit binds and activates adenylyl cyclase 4. Adenylyl cyclase synthesizes cAMP from ATP 5. Cyclic AMP binds to the two regulatory subunits of **Protein Kinase A** 6. The two catalytic subunits are set free to phosphorylate protein targets Meanwhile, the enzyme system responsible for glycogen synthesis is inactivated by cAMP pathway. PKA also phosphorylates the enzyme glycogen synthase and inactivates it

Question 44

Intracellular effects of the cAMP pathway (favorite it!)

Answer 44

Intracellular effects of the cAMP pathway: Control of glycogen degradation 1. Epinephrine binds beta-Adrenergic receptor 2. Gs protein binds GTP, dissociates from other subunits 3. Activated Gs binds and activates adenylate cyclase 4. Adenylate cyclase produces cAMP from ATP 5. PKA binds cAMP and becomes activated 6. PKA phosphorylates and activates Phosphorylase Kinase 7. Phosphorylase Kinase phosphorylates phosphorylase beta into the active phosphorylase alpha form 8. Phosphorylase alpha catalyzes the phosphorolytic cleavage of glycogen into glucose-1-phosphate

Question 45

Glucagon also stimulates? **Favorite!**

Answer 45

* Glucagon is a polypeptide hormone secreted by the a cells of the pancreatic islets of Langerhans. * Glucagon binds to high-affinity G protein-coupled receptors on hepatocytes and stimulates Gs signaling. * Glucagon receptors are **_NOT_** found on skeletal muscle

Question 46

PKA Also Phosphorylates Transcription Factors. Elaborate!

Answer 46

The free catalytic subunit of protein kinase A (PKA) translocates to the nucleus and phosphorylates the transcription factor CREB (CRE-binding protein), leading to expression of cAMP-inducible genes.

Question 47

Protein Phosphatases

Answer 47

Protein Phosphatases ## Footnote Protein phosphorylation is rapidly reversed by the action of protein phosphatases, which remove a phosphate group from molecules that were activated by phosphorylation.

Question 48

Cholera toxin poisoning disrupts?

Answer 48

Cholera toxin poisoningdisrupts normal Gs protein signaling Cholera toxin alters secretion of salts and fluid in the intestine, which is normally regulated by hormones that act through the Gs to alter intracellular cAMP levels. A portion of the cholera toxin is an enzyme that chemically modifies Gs, so that it can no longer hydrolyze GTP. Thus cAMP levels stay high and cells stimulate to secrete salts and water Cholera issues lies within the GI tract. The Details * Cholera A toxin is absorbed into mucosal cells, where it is processed and complexed with ARF (ADP-ribosylation factor), a small G-protein that is normally involved with vesicular transport. * Cholera A toxin is an NAD-glycohydrolase, which cleaves NAD and transfers the ADP ribose portion to other proteins. * It ADP-ribosylates the Gas subunit of heterotrimeric G-proteins, thereby inhibiting their GTPase activity. * As a consequence, they remain actively bound to adenylyl cyclase, resulting in increased production of cAMP. * The CFTR channel is activated, resulting in secretion of chloride ion and Na+ ion into the intestinal lumen. * The ion secretion is followed by loss of water, resulting in vomiting and watery diarrhea

Question 49

Odorant Receptors

Answer 49

Odorant Receptors * The largest family of G protein-coupled receptors are responsible for odor detection and recognition. * Odorant receptors are encoded by a large multigene family of hundreds of genes. * Odorant receptors stimulate adenylyl cyclase, leading to an increase in cAMP. * **cAMP binds to and opens Na+ (_ion)_ channels in the plasma membrane, leading to initiation of a nerve impulse.** basically Scent chemicals activate Gs and hence adenylate cyclase in scent-sensitive nerve cells. cAMP then opens a nonselective cation channel in the plasma membrane. ----------------------------------- Main 3 intracellular targets of cAMP are: * cAMP-dependent kinase or protein kinase A **(PKA)** * EPAC (Exchange Protein Activated by Cyclic AMP) * Ion Channels

Question 50

Gi Signaling

Answer 50

- Gi signaling can inhibit Adenylyl cyclase activity by the G alpha subunit - **Gi beta gama subunits act mainly by regulating ion channels** * For example stimulation of muscarinic acetylcholine receptors by acetylcholine released by the vagus nerve, results in the bg subunits binding to K+ channels in the heart muscle plasma membrane and opening them. - Whooping cough (pertussis) * The inhibitory protein Gi is inactivated by pertussis toxin, Gi can no longer inhibit adenylyl cyclases basically concerning whooping cough, If you inhibit an inhibitator, the downstream is left on. So Gi signaling, which would normally inhibit adenylyl cyclase, is inhibited by pertussis toxin.... and adenylyl cyclase activity continues… leading to the production of cAMP. whooping cough (pertussis) issues lies within the respiratory system. ------------------------------------- Gi shuts off Adenylyl cyclase activity , which means cAMP cannot be produced acetylcholine triggers activation of Gi. beta subunit of the heterotrimeric protein complex, becomes activated and they bind to targets such as calcium channels.

Question 51

Whooping Cough (Pertussis)

Answer 51

* Initial symptoms, similar to the common cold, usually develop about a week after exposure to the bacteria. * Severe episodes of coughing start about 10 to 12 days later. * In children, the coughing often ends with a "whoop" noise. * The sound is produced when the patient tries to take a breath. * The whoop noise is rare in patients under 6 months of age and in adults. * Often see uncontrollable fits, each with five to ten forceful coughs (“machine gun coughing”) * Coughing spells may lead to vomiting or a short loss of consciousness. * Pertussis should always be considered when vomiting occurs with coughing. * In infants, choking spells are common. * Other pertussis symptoms include: Runny nose, slight fever (102 °F or lower) and diarrhea

Question 52

Transducin (Gt) Signaling

Answer 52

Transducin (Gt) Signaling * Cyclic GMP (cGMP) is also an important second messenger in animal cells. * **cGMP is formed from GTP** by guanylyl cyclases and degraded to GMP by a **phosphodiesterase.** * In the vertebrate eye, **cGMP is the second messenger that converts _visual signals_ to nerve impulses.** * This process is controlled by the **Rhodopsin** (retinal component), **Transducin (Gt**) and a cGMP Phosphodiesterase. basically, Rhodopsin (vitamin A derivative called ratinal) activations when light hits it causing a conformational change-\> The associated heterotrimeric complex is called Gt (transducin), will become active by having the alpha subunit lose GDP and bind GTP, transducin will then go bind and activate cGMP phosphodiesterase…which will cleave cGMP….decreasing it’s level in the cell.

Question 53

Role of Transducin (Gt) in Photoreception

Answer 53

Role of Transducin (Gt) in Photoreception * The photoreceptor in rod cells of the retina is a G protein-coupled receptor called rhodopsin. 1. Rhodopsin is activated when light is absorbed by the associated small molecule retinal. 2. Rhodopsin then activates the G protein transducin (Gt); 3. The α subunit stimulates cGMP phosphodiesterase, leading to decreased levels of cGMP. 4. cGMP levels are translated to nerve impulses by a direct effect of cGMP on ion channels.

Question 54

Gq Signaling Extremely important! favorite it!!!

Answer 54

Gq Signaling 1. Ligand binds to receptor 2. Gq is activated 3. Gq then activates phospholipase C beta 4. PIP2 is cleaved into InsP3 (inosytal triphosphate and DAG by PhosphoLapase C beta. (diaceylglycerol is left behind after being cleaved from triaceylglycerol to diacylglerol. phosphate group went to make insP3 (inosytaltryphosphate)). 5. InsP3 binds to InsP3 receptor (ligand-gated calcium channel) in smooth ER. why? because at this point it has 3 phosphate groups and therefore has 3 negative charges...so it can easily be released into the cytosol and migrate to the smooth ER and bind to inosytal receptors and ...... 6. Calcium is released into cytosol and binds **calmodulin** (and other calcium vitamin binding proteins) and modulates other pathways 7. Meanwhile DAG (diaceyl glycerol which will stay with the membrain because it is hydrophobic) activates protein kinase C (PKC) **(-PKC activation also requires binding of calcium and phosphatidylserine)**...basically, DAG will bind to protein and ulter their behavior. 8. PKC then stimulates other pathways by phosphorylating proteins that mediate cell response. --------------------------------------------------------- Many G proteins use inositol triphosphate and diglycerol as second messengers **Phospholipase C cleaves PIP2 into inositol triphosphate and DAG** Many G proteins use inositol triphosphate and diacylglycerol as second messengers Phospholipase C cleaves PIP2 into inositol triphosphate and DAG so when you hear Gq, think inositol triphosphate and diacylglycerol and calcium (pic from slide 62)

Question 55

Prostaglandins

Answer 55

Typically activates G protein receptor (Gq) * Prostaglandins such as thromboxane A (TXA2) can stimulate Gq signaling pathways * Prostaglandins are synthesized from arachidonic acid. - Cyclooxygenases are key enzyme in the pathway * Aspirin blocks cyclooxygenases, thereby inhibiting synthesis of thromboxane A2 and other prostaglandins from arachidonic acid * Aspirin significantly reduces incidence of heart attacks by reducing blood clots

Question 56

Gq Signaling in Platelet Activation

Answer 56

* ADP released from damaged cells activates Gq receptors * This activates PLCb * PLCb cleave PIP2 into IP3 and DAG * IP3 binds and opens calcium channels associated with endoplasmic reticulum

Question 57

when Insulin binds to its receptor, what is the very first enzyme turned on?

Answer 57

Thyrocine kinase! Thyrocine kinase is the very first enzymed turned on when insuline binds to it's receptor.

Question 58

What do steroid hormones, thyroid hormone, vitamin D3, and retinoic acid(synthesized from vitamin A bind to?

Answer 58

They bind to intracellular receptors (transcription factors) leading to changes in gene expression.

Question 59

Steroid hormone receptors often have what kind of binding domains? (favorite it!)

Answer 59

Steroid hormone receptors often have Zinc finger DNA binding domains

Question 60

What is HAT? (favorite it!)

Answer 60

HAT stands for histone acetyltransferase. It puts acetyl groups onto histones. Histone are basic proteins that DNA rap tightly around. To get gene expression, you have to loosen the DNA that is rapped around the histone protein. So HAT's role is to bind acetyl groups onto histone. by doing this, DNA bind less tighly making it easier for DNA, on that portion of that part of the chromatin, to be transcribed.

Question 61

Platelet Activation

Answer 61

Platelet Activation The inositol trisphosphate gated calcium channel is a calcium-selective channel in the membrane of the endoplasmic reticulum. An increase of cytosolic calcium concentration in platelets makes them sticky, initiating blood clotting. Scanning electron micrograph of a blood platelet on the damaged inner surface of a blood vessel. The platelet has activated, extending short processes called pseudopodia, and is ready to initiate blood clotting

Question 62

Calcium & Signaling

Answer 62

Calcium & Signaling * The release of calcium ions is a key event in many signaling processes * Calcium functions as a ubiquitous (found everywhere) intracellular mediator * Calcium levels are very low in the cytosol * Ca2+ is actively pumped out of the cytosol to the cell exterior * Ca2+ is pumped out of the cytosol into the ER and mitochondria, and various molecules in the cytosol bind free Ca2+ tightly * The frequency of Ca2+ oscillations influences a cell’s response * Ca2+ is a versatile **second messenger** that controls a wide range of cellular processes. The fertilization of an egg by a sperm triggers an increase in cytosolic Ca2+

Question 63

Regulation of intracellular Ca2+ in electrically excitable cells Favorite it!

Answer 63

Regulation of intracellular Ca2+ in electrically excitable cells * Ca2+ is also increased by uptake of extracellular Ca2+ by regulated channels in the plasma membrane. * In electrically excitable cells of nerve and muscle, voltage-gated Ca2+ channels are opened by membrane depolarization. * The results is increase in intracellular Ca2+ signals that cause further release of Ca2+ from the ER by opening Ca2+ channels (**ryanodine receptors**) in the ER membrane. * **Ryanodine receptor** channels are important for amplifying calcium response * Ligand is calcium. * Binding of calcium induces the calcium channel to open

Question 64

The ryanodine receptor and its function in Ca2+ release during skeletal muscle contraction

Answer 64

The ryanodine receptor and its function in Ca2+ release during skeletal muscle contraction * The interaction of the α-subunit of the Ca2+ channel, also known as dihydropyridine receptor (DHPR), and the Ca2+ release channel of the SR called ryanodine receptor (RyR1) connects both membranes, transverse tubular (T-tubule) and SR membranes. * This connection is responsible for electromechanical coupling. * Several cytoplasmic and SR proteins are associated with the DHP/RyR complex (triadin, calsequestrin, FK506 binding protein, and calmodulin). * Calcium release from the SR via the RyR1 triggers muscle contraction and multiple cellular effects by binding of Ca2+ to a variety of other target proteins. * Reuptake of Ca2+ from the cytoplasm into the SR is carried out by the SR calcium pump. ---------------------------------------------------------------- additional information The ryanodine receptor and its function in Ca2+ release. Proposed arrangement of proteins in the SR and target proteins of Ca2+ in the cytoplasm. The transverse tubular membrane is part of the plasma membrane of the muscle fiber. The interaction of the α-subunit of the Ca2+ channel, also known as dihydropyridine receptor (DHPR), and the Ca2+ release channel of the SR called ryanodine receptor (RyR1) connects both membranes, tubular and SR membranes. This connection is responsible for electromechanical coupling. Several cytoplasmic and SR proteins are associated with the DHP/RyR complex (triadin, calsequestrin, FK506 binding protein, and calmodulin). Calcium release from the SR via the RyR1 triggers muscle contraction and multiple cellular effects by binding of Ca2+ to a variety of other target proteins. Reuptake of Ca2+ from the cytoplasm into the SR is carried out by the SR calcium pump. (pic from slide 71)

Question 65

Malignant Hyperthermia Favorite it!

Answer 65

Malignant Hyperthermia * Malignant hyperthermia is an autosomal dominant condition in which there may be a dramatic adverse response to the administration of many commonly used inhalational anesthetics (e.g., halothane) and depolarizing muscle relaxants such as succinylcholine. * Malignant hyperthermia is most frequently associated with mutations in the gene for the Ryanodine receptor 1 * Soon after induction of anesthesia, the patients develop life-threatening fever, sustained muscle contraction, and attendant hypercatabolism. * Increased levels of ionized calcium in the sarcoplasm of muscle after drug exposure. * This increase leads to muscle rigidity, elevation of body temperature, rapid breakdown of muscle (rhabdomyolysis), and other abnormalities. * The condition is an important if not a common cause of death during anesthesia.

Question 66

The calcium-calmodulin complex

Answer 66

The calcium-calmodulin complex * In the cytosol, calcium binds to proteins like calmodulin. * Calmodulin is one of the most important calcium-binding proteins in the cell and can constitute as much as 1% of the total protein mass. * When calmodulin is activated after binding calcium, it targets and regulates kinases and phosphatases

Question 67

Calcium-calmodulin-dependent protein kinases (CaM-Kinases) mediate many of the responses to?

Answer 67

Calcium-calmodulin-dependent protein kinases (CaM-Kinases) mediate many of the responses to Ca 2+ signals in animal cells * CaM-kinases are a family of serine/threonine kinases * Some CaM-kinases phosphorylate gene regulatory proteins, such as CREB protein * CaM-kinase II is enriched in the nervous system and is highly concentrated in synapses when calcium binds to calmodulin, now it can form a complex with caM-kinase and activate it. caM-kinase autophosphoylates making it fully active. once it is fully active, you can see that it can dissociate and still have some activity. but once you di-phosphorylate it and it is no longer bound to calmodulin, then it reverts back to the inactive state.

Question 68

Nitric oxide (NO)

Answer 68

* Nitric oxide (NO) is a paracrine signaling molecule in the nervous, immune, and circulatory systems, which alters the activity of enzymes. * NO is synthesized from arginine by nitric oxide synthase. * Nitric Oxide (NO) produced by NO synthase, which converts amino acid arginine to NO and citrulline * Its action is restricted to local effects because it is extremely unstable, with a half-life of only a few seconds. * NO stimulates guanylyl cyclase to make cGMP

Question 69

Nitric Oxide couples _____________ in endothelial cells to\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ in blood vessels

Answer 69

Nitric Oxide couples _G protein-linked receptor stimulation_ in endothelial cells to _relax smooth muscle cells_ in blood vessels * NO is involved in dilation of blood vessels. * Neurotransmitters released from nerve cells in the blood vessel wall stimulate NO synthesis by endothelial cells. * NO diffuses to smooth muscle cells, activates guanylyl cyclase, resulting in synthesis of cyclic GMP, which induces muscle cell relaxation and blood vessel dilation.

Question 70

How acetylcholine induces smooth muscle relaxation Favorite it!

Answer 70

How acetylcholine induces smooth muscle relaxation * Acetylcholine binds to heptahelical receptor and triggers Gq signaling in the endothelial cells * Calcium is released into the cytoplasm from the sER * Calcium binds calmodulin * Calmodulin activates endothelial Nitric Oxide synthases * Nitric Oxide synthase creates NO and citrulline from Arginine * NO diffuses out of the endothelial cells and into the smooth muscle cell * NO binds and activates Guanylyl cyclase * Guanylyl cyclase synthesizes cGMP from GTP * cGMP activates Protein Kinase G resulting in smooth muscle relaxation so as a overall, there are two subpopulations...endothelial and smooth muscles. what was the role of endothelial? make NO (nitric oxide). what was the role of smooth muslce? to respond to Nitric oxide produced by the endothelial and relax. by giving nitroglycerine, you can skip endothelial cells because nitroglycerine will decompose to nitric oxide for smooth muscle.

Question 71

NO, erectile dysfunction and angina pectoris **Favorite it!**

Answer 71

NO, erectile dysfunction and angina pectoris * Nitroglycerin for angina to release constricted coronary arteries. * Glycerol trinitrate decomposes to NO, which activates a guanylyl cyclase. * This will relax arterial smooth muscle cells * Viagra (sildenafil): an **inhibitor of cGMP-**specific phosphodiesterase (breakdown of cGMP) * Nitric Oxide released by the neurons in the penis results in the blood vessel dilation responsible for penile erection. * Viagra helps maintain elevated cGMP in erectile tissue, this pathway is stimulated for a longer time period following NO release. inside the smooth muscles, what was the second messenger that was critical to maintaining smooth muscle relaxation? cGMP. when you give sildenafil (viagra) you will maintain elevated levels of cGMP because cGMP-specific phosphodiesterase is inhibited.

Question 72

Introducing cyclic Methylxanthines does what to the amount of cAMP in a cell?

Answer 72

Introducing cyclic Methylxanthines increases the amount of cAMP in the cell because Methylxanthines are **cAMP phosphodiesterase inhibitors!** Because Methylxanthines inhibits phosphodiesterase inhibitors, phosphodiesterase inhibitors are not around to cleave cAMP.

Question 73

Ion channels is important in (in regards to cell signaling)?

Answer 73

Ion channels is important in g protein’s role in smelling things.

Question 74

Gluconeogenesis

Answer 74

Gluconeogenesis results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol and glucogenic amino acids.

Question 75

Glycogenolysis

Answer 75

Glycogenolysis is the breakdown of glycogen polymers into glucose monomers.

Question 76

Lipolysis

Answer 76

Lipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into free fatty acids followed by further degradation into acetyl units by beta-oxidation. ## Footnote

Question 77

4 PKA targets

Answer 77

4 PKA targets 1) Phosphorylase kinase 2) Glycogen syntase 3) Creb (is a transcription regulator that can be phosphorylated by PKA 4) CFTR

Question 78

DAG

Answer 78

diacylglycerol activates protein kinase C (PKC). but to do this, it needs to bind to calcium and phosphotidyl serine.

Question 79

Ryanodine receptor 1

Answer 79

Ryanodine receptor 1 causes release of calcium in the condition called malignant hyperthermia

Question 80

another enzyme in addition to myosin light chain kinase that we know can be regulated by calmodulin.

Answer 80

another enzyme in addition to myosin light chain kinase that we know can be regulated by calmodulin is caM-kinase. How do we activate it? calcium binds to calmodulin...and calmodulin forms a complex with caM-kinase. ---------------------------------------------- A Reminder! Calcium-calmodulin-dependent protein kinases (CaM-Kinases) mediate many of the responses to Ca 2+ signals in animal cells CaM-kinases are a family of serine/threonine kinases Some CaM-kinases phosphorylate gene regulatory proteins, such as **CREB** protein CaM-kinase II is enriched in the nervous system and is highly concentrated in synapses when calcium binds to calmodulin, now it can form a complex with caM-kinase and activate it. caM-kinase autophosphoylates making it fully active. once it is fully active, you can see that it can dissociate and still have some activity. but once you di-phosphorylate it and it is no longer bound to calmodulin, then it reverts back to the inactive state.