Cell Signaling Flashcards

Question

Tyrosine kinase-linked receptors

Answer 1

Lack enzymatic activity, but when bound by a ligand they associate with and activate and intracellular tyrosine kinase which acts on intracellular proteins to alter their activities. ## Footnote Most cytokines signal via tyrosine kinase-linked receptors coupled to the **JAK/STAT pathway**

Answer 2

i. Receptors with an intracellular guanylate cyclase domain ii. Activation of the cyclase domain **increases cGMP**, as a second messenger iii. Only two:**Atrial natriuretic factor (ANF) receptors** and **guanylin receptors**

Answer 3

i. Receptors with and intracellular tyrosine phosphatase domain ii. Activation of the domain removes phosphate groups from tyrosine side-chains in proteins to alter their functions

Answer 4

i. Receptors with an intracellular serine/threonine kinase domain ii. Ligand binding activates the ser/thr kinase domain iii. Receptors for **transforming growth factor beta (TGF-beta)** and **bone morphogenic protein (BMP)** families iv. Regulate activity of SMAD transcription factors

Answer 5

i. Receptors with an intracellular tyrosine kinase domain. Ligand binding activates the kinase domain. ii. Signaling involves **adaptor proteins** to connect to diverse signaling pathways such as the **RAS/MAP kinase pathway** iii. Well known examples = **insulin receptor** and **epidermal growth factor (EGF)** receptor family iv. In general, polypeptide (50-400 a.a.) **growth factors activiate RTKs**

Answer 6

1. An **immediate change in cellular metabolism** by activating or inhibiting enzymes or stimulating the uptake of metabolites 2. The opening or closing of ion channels resulting in a **change in the electrical charge across the plasma membrane** 3. A **change in gene expression**

Answer 7

1. Reducing the signaling molecules availability in the extracellular space 2. Internalizing and degrading the receptors 3. Rapidly modifying the receptor (e.g. phosphorylation) so that it becomes inactive or desensitized 4. Activating the expression of a gene coding for an inhibitor of the signaling pathway

Answer 8

Aka HREs - The receptor-hormone complex alters transcription of susceptible genes by binding (as homo/heterodimers) to regulatory gene sequences collectively known as HREs Glucocorticoid response element (GRE) Estrogen response element (ERE) Vitamin D response element (VDRE)

Answer 9

1. Reproduction - estrogen receptors, progesterone receptors, androgen receptors 2. Glucose metabolism and stress - glucocorticoid receptor (GR) 3. Mineral balance - mineralcorticoid receptor (MR) 4. Thyroid function - thyroid hormone receptor (TR) 5. Lipid metabolism - liver x receptor (LXR) and peroxisome proliferator-activated receptors (PPARs)

Answer 10

1. N-terminal transactivation domain 2. A central DNA binding domain, containing two zinc finger DNA binding motifs 3. A C-terminal ligand/hormone-binding domain

Answer 11

Steroid receptor subclass (GR, MR, PR, AR, and ER)

Answer 12

Activation - due to the recruitment of co-activator proteins by the hormone-receptor complex (co-activators often have HAC activity) Repression - is due to the recruitment of co-repressors by some unliganded nuclear receptor (co-repressors often have HDAC activity)

Answer 13

Antagonist of progesterone receptors

Answer 14

**Rosiglitazone (Avandia), pioglitazone (Actos)**- are usued as antidiabetic drugs. TZDs bind to peroxisome proliferator-activated receptor (PPAR)-ƴ, which forms heterodimers with retinoic acid receptor (RXR) and binds to PPREs in the promoters of genes inolved with control of glucose and lipid metabolism in muscle, adipose, and liver.

Answer 15

**Tamoxifen** and **raloxifene** - Fx as agonist or antagonists of estrogen receptors depending upon cell type. Used to treat estrogen-dependent breast cancers. Tamoxifen binds to ER but does not induce the same conformational change as estrogen that is necessary for interaction with co-activator proteins

Answer 16

1. Excessive hormone production 2. Insufficient hormone production 3. Receptor defects and/or downstream defects (sometimes referred to as "hormone resistance")

Answer 17

T3 - tri-iodothyronine Functions - increase oxidative metabolism and increase basal metabolic rate (BMR) Analogy: thyroid gland functions as the body's thermostat (turned up - burn more fuel and prouduce more heat)

Answer 18

Synthesized by follicular cells in the thyroid gland by iodination and coupling of tyrosines in thyroglobulin by tyrosine peroxidase (TPO) ## Footnote Thyroid gland secrete mostly T4 -> peripheral tissues deiodinate T4 to produce circulating T3

Answer 19

sxs: Weakness, fatigue, and lethary due to diminished utilization of oxidative fuels Cold intolerance due to reduced BMR and reduced heat production Weight gain due to stored fuels not being utilized Dry skin and coarse hair due to reduced metabolic activity of sebaceous glands Elevated LDL (LDL_C) due to redueced LDLR expression in liver (LDLR gene is upregulated by thyroid hormone)

Answer 20

LDLR on hepatocytes bind and internalize LDL_C removing it from the blood

Answer 21

Levothyroxine (synthetic T4) Iodine supplement for iodine deficiency Surgery for tumors Immune modulation for autoimmune conditions Management of other hormone deficiencies for secondary or tertiary hypothyroidism cases, if present

Answer 22

Primary hypothyroidism (↓T3/T4→ ↑TSH): Hashimoto's thyroiditis, iodine deficiency Secondary hypothyroidism ( ↓TSH → ↓T3/T4): pituitary defect Tertiary hypothyroidism( ↓TRH→↓TSH →↓T3/T4): hypothalamus defect

Answer 23

Dx: Low T4, elevated TSH, and low urinary iodine Tx: iodine supplementation ## Footnote Primary hypothyroidism

Answer 24

~90% of hypothyroidism Dx: low T4 and elevated TSH, + for anti-thyroid antibodies (anti-TPO and/or anti-thyroglobulin antibodies) Tx: HRT w/ levothyroxine ## Footnote Primary hypothyroidism

Answer 25

Causes: pituitary tumors or damage from surgery/radiation therapy Dx: low T4, low TSH, negative for anti-thyroid antibodies Dx: may require more specialized tests and MRI

Answer 26

Causes: Tumors (especially craniopharyngiomas) and TBI causing broad hypothalamic dysfunction Dx: low/low-normal T4, low or inapporpriately normal TSH, low TRH (requires specialized testing/imaging) ## Footnote Tertiary hypothyroidism

Answer 27

sxs: Weight loss (despite normal appetite) due to increased BMR, Tachycardia, nervousness, anxiety, due to increased expression of of β-adrenergic receptors causing an enhanced response to catecholamines Perspiration and heat intolerance due to increased BMR Goiter may develop in some cases Tx: Methimazole and propylthiouracil inhibit thyroid peroxidase (TPO), and enzyme crucial for thyroid hormone synthesis Thyroidectomy or ablation w/ radiotactive iodine therapy (Pt's require daily oral levothyroxine afterward) Immunosupression for autoimmune disorders

Answer 28

1. Primary: Graves disease, toxic multinodular goiter, toxic adenoma 2. Secondary: TSH secreting pituitary tumors 3. Tertiary: Hypothalmic dysfunction

Answer 29

60-80% of hyperthyroidism Autoimmune disorder in which auto-antibodies stimulate secretion of thyroid hormones Dx: high T4 and low TSH (due to negative feedback), **positive for anti-TSH receptor antibodies** (stimulate the TSH receptor activity) Sxs: Exopthalmos is common (results from the underlying autoimmune disease affecting volume of the orbital soft tissues - antibodies stimulate fibroblasts in the eye) Tx: immunosuppressive drugs (corticosteroids) are needed to treat exopthalmos ## Footnote Primary hyperthyroidism

Answer 30

aka Plummer's disease Results from multiple autonomously functioning nodules in the thyroid - develops gradually over many years Dx: high T4 and low TSH, imaging studies (US or radioiodine uptake scans) ## Footnote Primary hyperthyroidism

Answer 31

A single hyperfunctioning thyroid nodule that produces excess thyroid hormones Dx: high T4 and low TSH, imaging studies (US or radioiodine uptake) ## Footnote Primary hyperthyroidism

Answer 32

Causes: pituitary tumors secreting TSH (aka "central hyperthyroidism") Dx: high T4 and high TSH, MRI

Answer 33

Causes: hypothalmic dysfunction - extremely rare and not well-documented in medical literature Dx: high T4 and high TSH (TRH is not routine thyroid blood testing but would be elevated) Dx require imaging and specialized testing of hypothalmic-pituitary-thyroid axis

Answer 34

**Cortisol** Fx: promotes gluconeogensis, enhances protein breakdown, stimulates lipolysis. A counter-regulatory hormone (oppose the effects of insulin and raises blood glucose) Immunosuppressive effects ## Footnote Corticosteroids

Answer 35

**Aldosterone** Fx: promotes Na reabsorption and K excretion in the kidney

Answer 36

1. Hypothalamus releases corticotropin releasing hormone (CRH) 2. CRH stimulate anterior pituitary to release of adrenocorticotropic hormone (ACTH) 3. ACTH stimulates adrenal cortex to produce cortisol 4. Cortisol binds to glucocorticoid receptors (GR) inside cells and alters transcription of genes containing GREs 5. Cortisol provides negative feedback to hypothalamus and pituitary (↓CRH and ACTH production)

Answer 37

Release of aldosterone from the adrenal glands is primarily stimulated by factors within the renin-angiotensin-aldosterone system (RAAS) Aldosterone binds to the mineralcorticoid receptor (MR) which then alters transcription of genes with MREs

Answer 38

Aka adrenal insufficiency Sxs: fatigue, anorexia, hypoglycemia due to low gluconeogenesis Hyponatremia, hyperkalemia due to low aldosterone **Hyperpigmentation** (darkening of the skin and mucous membranes) **if ACTH is very high** -ACTH has similarity with melanocyte-stimulating hormone (MSH) and stimulate production of melanin Tx: Low cortisol: HRT w/ hydrocortisone or prednisone (synthetic glucocorticoids) Low aldosterone: HRT w/ fludrocortisone (synthetic mineralcorticoid) and **maintenance of sodium intake** Management of other hormone deficiencies if present and Tx of underlying cause if possible

Answer 39

Addison's disease (destruction of adrenal cortex by infectious disease - i.e. TB or autoimmune Dx: low cortisol, low aldosterone, **high ACTH** No response to ACTH stimulation test - synthetic ACTH (cosyntropin) is given IV and cortisol levels are measured. A normal response is a significant increase in serum cortisol.

Answer 40

Secondary adrenal insufficiency: pituitary defect (tumor, TBI, surgery or radiation) Dx: low cortisol and low ACTH inadequate or subnormal response to ACTH stimulation test - adrenal glands have often atrophied due to long-term lack of ACTH stimulation Electrolytes (Na and K) are typically normal (aldosterone is not strongly regulated by ACTH) May show levels of other pituitary hormones (hypopituitarism)

Answer 41

Hypothalamus defect Often part of broader hypothalamic dysfunction due to tumors, TBI, radiation Dx: low cortisol, low-normal ACTH (depending on severity of hypothalamus defect) Normal response to CRH stimulation test - ACTH and cortisol levels increase after CRH administration. **This response distinguishes tertiary from secondary adrenal insufficiency**

Answer 42

**Cushing's syndrome** Sxs: **Muscle weakness, skin thinning, stretch marks** due to protein breakdown **Hyperglycemia** due to ↑ gluconeogenes **Hypertension** due to ↑ sodium retention and consequent water reabsorption coupled with enhanced sensitivity of blood vessels to catecholamines **Hirutism** due to stimluation of androgen production

Answer 43

Result of receiving high doses or long-term tx w/ corticosteroids

Answer 44

**aka ACTH-independent Cushing's syndrome** Causes: adrenal tumor produces excess cortisol, independent of pituitary control Dx: **high cortisol, low ACTH** (suppressed by - feedback) No response to Dex suppression test - Dex is a potent synthetic glucocorticoid that, under normal conditions, supresses ACTH production in the pituitary and lowers cortisol. Failure to supress indicates source of cortisol is not responsive to pituitary feedback mechanisms Noninvolved adrenal gland may atrophy due to lack of ACTH stimulation

Answer 45

Cushing's disease Dx: high cortisol and high ACTH (usually not as high as in Addison's disease, so no hyperpigmentation) A low dose dex (1mg) will not suppress cortisol, but a high-dose dex (8mg) does - the pituitary tumor retains some sensitivity to negative feedback ## Footnote Secondary hypercortisolism

Answer 46

i.e. small cell lung cancer - Cushing syndrome not disease Dx: **high cortisol and high ACTH** (usually not as high as in Addison's disease, so no hyperpigmentation) Cortisol not supressed by low or high-dose dex. The tumore produces ACTH autonomously Both **adrenals can be enlarged** due to persistent stimulation by ACTH ## Footnote Secondary hypercortisolism

Answer 47

Hypothalmic dysfunction → ↑CRH Causes: long-term exogenous glucocorticoid use leads to supression of the hypothalamic-pituitary-adrenal (HPA) axis. Upon withdrawal of exogenous steroids, the hypothalamus may overproduce CRH. This leads to excessive ACTH production by the pituitary and subsequently increased cortisol production by the adrenals. Dx: may involve CRH stimulation tests and careful monitoring during steroid tapering Tx: gradual tapering of exogenous glucocorticoids. Temporary replacement w/ shorter-acting glucocorticoids

Answer 48

Inherited defects are rare but clinically significant Sxs: resemble hormone deficiency, despite elevated hormone levels Tx: if the inactivation is partial, the condition can sometimes be treated w/ high doses of hormones 1. Generalized thyroid hormone resistance - mutations in the TR gene that reduces T3 binding - hypothyroidism sxs w/ high T3/4 levels and high TSH (- feedback mech needs function TR to work correctly) 2. Glucocorticoid receptor deficiency - loss of Fx mutations in the GR gene (Addison's disease-like sxs w/ high cortisol)

Answer 49

Synthesized by the deamination of arginine by NO synthase Activates a cytosolic guanylate cyclase resulting in the production of the second messenger cyclic guanosine monophosphate (cGMP) Increase in cGMP levels activated cGMP-dependent protein kinases, culminating in a reduction in intracellular Ca²⁺ conc. and decrease to the sensitivity of the contractile system to Ca²⁺

Answer 50

Selectively inhibit the type 5 PDE (PDE5) - highly express in vascular smooth muscle cells. Viagra is less selective for most other types of PDE, like PDE3 (predominantly expressed in cardiac muscle). However, sildenafil is only slightly more selective for PDE5 than for PDE6, the predominant PDE in light-sensing cells of the retina Thus, slight overdoses of sildenafil can cause mild alterations in visual color perception due to inhibition of retinal PDE6, which manifests as cyanopsia (blue-tinted vision)

Answer 51

There have also been at least 14 reported cases of temporary blindness associated with Viagra use due to nonarteritic anterior ischemic optic neuropathy. It is thought that these cases arise because the optic nerves are pinched by Viagra-induced dilation of ophthalmic arteries in the optic foramen.

Answer 52

7 transmembrane helices Activate heterotrimeric guanine-nucleotide binding proteins (G-proteins) to control specific effector proteins

Answer 53

Have three subunits (α, β and γ) When activated - G-protein interacts with an effector protein which produces a 2nd messenger moecule (effector proteins are usually enzymes or ion channels) α subunits can bind GDP or GTP -α_GDP is inactive -α_GTP is active Agonist binding to a GPCR results in a conformational change that promotes interaction with an inactive G-protein (α_GDPβγ). - induces conformational change that promotes interaction with inactive G-protein α_GTP dissociates from βγ and interacts with an effector protein altering its activity α contains an intrinsic GTPase activity which hydrolyzes GTP to GDP. The α-GDP then reassociates with βγ to form an inactive α_GDPβγ complex. The GTPase activity functions as a self-timer or "auto-off" switch for the α subunit.

Answer 54

The 3 major Gα families: α_s, α_i,α_q (aka Gs, Gi, and Gq) Gs and Gi modulate adenylate cyclase to alter levels of 3',5'-cAMP: Gs - stimulates adenylate cyclase to increase cAMP Gi - inhibits adenylate cyclase to decrease cAMP

Answer 55

cAMP is degraded by cAMP phosphodiesterases - in the absence of Gs signaling cAMP levels levels are kept low. Rapid formation and degradation of 2nd messengers allows for rapid on/off control -Methyl xanthines, like caffeine and theophylline, inhibit cAMP phosphodiesterases and pontentiate the effects of GCPRs coupled to Gs. (Note: the primary physiological effects of caffeine are due to antagonism of adenosine receptors in the CNS)

Answer 56

is the result of simultaneous action of Gs and Gi signals

Answer 57

Activated by cAMP PKA is a tetramer with two regulatory (R) and two catalytic (C) subunits When cAMP levels rise, cAMP binding sites in the R subunits become occupied and the C subunits dissociate as active ser/thr kinases PKA regulates the activites of secondary kinases and phosphatases, with change pohsphorylation states of various enzymes turning them on or off. A classic example is regulation of glycogen synthesis and breakdown in the liver

Answer 58

Active PKA inactivated glycogen synthase

Answer 59

Performed by PKA - phosphorylated CREB binds to specific DNA sequences, cAMP regulatory elements (CRE), in the promoters of some genes to produce changes in gene expression

Answer 60

Activates phospholipase C (PLC). PLC cleaves phosphatidyl inositol bisphosphate (PIP2) in the membrane giving rise to 2nd messengers:**inositol triphosphate (IP3)** and **diacylglycerol (DAG)** IP3 diffuses in the cytosol and binds to IP3-gated Ca²⁺ release channels on Ca²⁺ storage organelles (sarcoplasmic and endoplasmic reticulum) causing an increase in cytosolic Ca²⁺ which activates calcium-dependent processes

Answer 61

Cushing's syndrome

Answer 62

Decrease PKA activity

Answer 63

Phospholipase C will be activated

Answer 64

Modulation of gene transcription

Answer 65

T3 - LDLR gene has a T3 binding region that upregulates expression ## Footnote Why there are diminished LDLR's in hepatocytes of someone with hypothyoroidism

Answer 66

Dimerization of SMAD factors

Answer 67

A) PI-3K Goes on to activate Akt and PKC

Answer 68

Alpha subunits of heterotrimeric G proteins

Answer 69

Bind to proteins that have a phosphotyrosine residue within a specific context

Answer 70

D) increased production of cGMP

Answer 71

C) activation of ctyosolic kinases that phosphorylate STAT proteins

Answer 72

A) the ability to phosphorylate tyrosine residues on proteins

Answer 73

Grb2 binds to phosphorylated tyrosine residues of the receptor

Answer 74

B) phosphaatidylinositol 4,5-bisphophate (PIP2) is a substrate

Answer 75

E) GTP'ase activating proteins (GAPs)

Answer 76

It is a tyrosine kinase

Answer 77

Bound to GDP - off Bound to GTP - on

Answer 78

The JAK/STAT pathway

Answer 79

slight overdoses of sildenafil can cause mild alterations in visual color perception due to inhibition of retinal PDE6, which manifests as cyanopsia (blue-tinted vision). ## Footnote selectively inhibit the type 5 PDE (PDE5) that is highly expressed in vascular smooth muscle cells. **Viagra is less selective** for most other types of PDE, like PDE3 predominantly expressed in cardiac muscle. However, Viagra is only slightly more selective for PDE5 than for PDE6, the predominant PDE in light-sensing cells of the retina.

Answer 80

Gs - cholera Gi - whooping cough ADP-ribosylation