Biochem Week 2 Flashcards
(42 cards)
Describe cell signaling:
Internal or external stimuli tell the body to react. This signal needs to be sensed and transmitted to individual cells in target organs and tissues This is done by chemical messengers and is called cell signaling
Describe/Draw a generalized signal-transduction cascade.
- release of chemical messenger 2. reception of chemical messenger (where is it*) 3. delivery of message inside the cell 4. signal transduction by: a) signal transducer proteins b) second messengers 5. activation of effectors that alter a physiological response 6. termination of the signal (if it can’t get turned off it is diseased)
Explain how signal transduction is amplified:
Secondary messengers amplify the signal, can diffuse, and have a fast response relative to proteins that turn genes on. - A ligand to a single receptor at the cell surface may end up causing massive changes in the biochemical activities within the cell. Enzymatic cascade amplify signal: enzyme 1 turns on multiple enzyme 2, which in turn all of the #2 turn on #3, while #1 continues to turn on more #2’s
Name types of second messengers:
Second messengers are nonprotein molecules 1. Phosphatidylinositol signaling 2.cAMP 3.Ca2+
Identify the five major types of chemical messengers
Neuropeptides: nervous system Hormones: endocrine system Cytokines: immunes system Eicosanoids: injury Growth Factor: cell proliferation a. The nervous system secretes two types of messengers: small-molecule neurotransmitters (such as acetylcholine) and neuropeptides (normally small peptides between 4 and 35 amino acids in composition). b. Endocrine system hormones consist of polypeptide hormones (such as insulin and glucagon), catecholamines (such as epinephrine), steroid hormones (derived from cholesterol, such as estrogen), and thyroid hormone. c. The immune system utilizes the messengers known as cytokines, which are small pro-teins with an average molecular weight of 20 kDa. There are different classes of cytokines (such as interferons, interleukins, tumor necrosis factors, and colony-stimulating factors), but all are secreted by the cells of the immune system and will induce alterations in gene transcription in the target cells. d. The eicosanoids are derived from long-chain fatty acids, and consiste of the prostaglan-dins, thromboxanes, and leukotrienes. e. Growth factors are polypeptides that function through the stimulation of cellular proliferation (hyperplasia) or cell size (hypertrophy).
Describe the three modes of action chemical messengers used to signal
Endocrine: through the blood (hormones) Paracrine: adjacent cell (axon and dendrites, immune system) Autocrine: same cell (often paracrine can be performed by a autocrine cell)
Describe intracellular transcription factor receptors, and where they reside:
Intracellular transcription factor receptor: Receptor can be cytosolic or nuclear and the chemical messenger is lipophilic (can diffuse through membranes). Turns genes on and off. Slow = takes hours to days for effect (thyroid hormones)
How do steroid hormone/thyroid hormone receptors function intracellularly?
1) These lipophilic molecules are transported in the blood bound to serum albumin, or to more specific transport proteins, such as steroid-hormone-binding globulin, or thyroid-binding globulin.(2) Once in the cell the lipophilic messenger binds to its receptor, which will often dimerize (with other intracellular transcription factors) to bind to the promoter-proximal regions of DNA to alter gene expression.
How does cortisol bound to its receptor functions at the level of gene transcription?
Because of the intracellular function, once in the cell and bound to its cytoplasmic receptor, the cortisol will enter the nucleus and will alter gene encoding. Specifically it increases transcription of genes encoding enzymes that raise blood glucose levels
cortisol pathway:
- cortisol binds to GR (glucocorticoid receptor)
- two bound GRs dimerize and undergo confirmational chnage to reveal DNA binding domain
- DNA binds to zinc finger DNA binding domain
- increased of transcription of genes encoding enzymes, raise blood glucose levels
Identify the three major classes of plasma membrane receptors and describe their common feature
Ion channel, kinase or bind kinase, and heptahelical Common features for plasma membrane receptors: 1) Extracellular domain that binds the chemical messenger 2) membrane spanning region 3) conformational change in the receptor 4) intracellular domain that initiates signal transduction/secondary messengers (fast response)
Describe an ion channel:
Ion channel: the neurotransmitter binds with the receptor and alters the conformation of the protein, which opens the ion-channel, allowing extracellular ions to go into the cell. The ion permeability of the plasma membrane is altered, and this will instantaneously convert the extracellular chemical signal into intracellular electric signal, which will alter the excitability of the cell. (fast response) - nervous system, muscles 1. Signal transduction consists of a conformational change when a ligand binds, which allows ion-flow through the channel 2. The acetylcholine receptor is an example of an ion-channel receptor.
Describe the common feature of the kinase/bind kinase receptor and signaling cascade:
The common feature of this class of receptors is that the intracellular kinase domain of the receptor (or the kinase domain of the associated protein) is activated when the messenger binds to the extracellular domain. The signal transduction pathway is propagated downstream through signal transducer proteins that bind to the activated messenger–receptor complex.
Describe heptahelical receptor/g-protein coupled receptor:
In addition to transporting small molecules, membrane proteins can also function as receptors. G-protein coupled receptors, the most important class of cell membrane receptors, are proteins that traverse the plasma membrane seven times (seven-pass receptors). They are coupled to trimeric GTP-binding proteins (G proteins), which are composed of three subunits: α, β, and γ. The G proteins are found on the cytosolic face of the membrane and serve as relay molecules. G-protein coupled receptors have extremely diverse functions and respond to a vast array of stimuli. However, all G-protein coupled receptor signaling is transduced via a similar mechanism. When the receptor is inactive, the α subunit (active subunit) of the G protein is bound to GDP. When the receptor is stimulated, a change in conformation causes the α subunit to exchange GDP for GTP, thereby releasing itself from the βγ complex. Once released, it binds and activates target proteins. α Subunit activity is short-lived, however, because the GTPase quickly hydrolyzes GTP to GDP, resulting in its inactivation. The target proteins activated by the α subunit vary, depending on which of the three main types of G protein is involved.
Describe Ion channels and their biochemical characteristics and functions: Example: the nicotinic acetylcholine receptor
Biochemical characteristic: The channel opens and Na+ ions flood down the electrochemical gradient into the cell Functions: The activation of receptors by nicotine modifies the state of neurons through two main mechanisms. On one hand, the movement of cations causes a depolarization of the plasma membrane (which results in an excitatory postsynaptic potential in neurons), but also by the activation of voltage-gated ion channels. On the other hand, the entry of calcium acts, either directly or indirectly, on different intracellular cascades leading, for example, to the regulation of the activity of some genes or the release of neurotransmitters.
Describe the general structures of the receptor tyrosine kinases and the process that converts them from inactive proteins to active enzymes
Receptor tyrosine kinase (RTK) is composed of an extracellular domain, which is able to bind a specific ligand, a transmembrane domain, and an intracellular catalytic domain, which is able to bind and phosphorylate selected substrates. Binding of a ligand to the extracellular region causes a series of structural rearrangements in the RTK that lead to its enzymatic activation.
Define autophosphorylation and its role in the signal-transduction process:
Occurs by the addition of a phosphate group to serine,threonine or tyrosine residues within protein kinases, normally to regulate the catalytic activity Protein kinases, many of which are regulated by autophosphorylation, are vital in controlling the cellular proliferation, differentiation, metabolism, migration and survival. Mutations in the genes encoding them or their potential activators or repressors can affect any number of functions within an organism. Phosphorylation is easily reversed by phosphatases. Therefore, it is an effective method of turning on' and off’ kinase activity.
Explain the role of SH2 domains in tyrosine kinase function
The function of SH2 domains is to specifically recognize the phosphorylated state of tyrosine residues, thereby allowing SH2 domain-containing proteins to localize to tyrosine-phosphorylated sites. This process constitutes the fundamental event of signal transduction through a membrane, in which a signal in the extracellular compartment is “sensed” by a receptor and is converted in the intracellular compartment to a different chemical form, i.e. that of a phosphorylated tyrosine.
Why can a mutations in Ras result in cancer?
Mutations can cause Ras to be active all the time, this in turn causes signaling cascade to always be on leading to tumor growth and cancer (ras is apart of the epidermal growth factor kinase cascade)
Describe insulin signaling and its function
It is unique that the insulin receptor is already a dimer and has an alpha and beta part to the receptor. It also requires IRS before a kinase pathway can be activated. The insulin receptor can activate MAP kinase pathway AND the protein kinase B (Akt) pathway
- Insulin signaling increases the number of glucose transporters at the plasma membrane
- The activation of PK B (Akt) promotes cell survival (antiapoptotic), as well as propagating some specific insulin effects
Describe common examples of ion channel pathologies in the following:
- Neuromuscular junction
- CNS
- General effect:
1.) Neuromuscular junction:
- Cobra venom blocks the receptor, could lead to suffocation (competitive inhibition, decrease muscle tone can lead to suffication)
- Suxamethonium bind receptor: short term muscle relaxant that aid endotracheal intubation
2) CNS - nicotine binds receptors (increases neurotransmitters available to bind and activates reward circuits)
* Myasthenia gravis is a neuromuscular disorder due to an autoimmune condition that produces antibodies against the acetylcholine receptor. The receptor cannot be activated by acetylcholine, and the muscle cell cannot respond to the neurotransmitter, and contraction will not occur. The overlying symptom of this disorder is muscle fatigue. The treatment consists of acetylcholines-terase inhibitors (such that acetylcholine is present for an extended period at the neuromuscular junction) and immunosuppressants to reduce the production of the antibodies targeted against the receptor. (competitive inhibition)
3) General Effect:
- Malathion poisoning (insecticide) bind acth prohibiting breakdown and termination of signal
- Sarin gas, same as above, but more toxic (competitive inhibition)
Describe the structure of the insulin receptor (IR) and the significance of the insulin-dependent dimerization of the receptor.
Always present as a dimer, insulin binds - conformation change through to the transmembrane protein, autophosphorylation of beta subunits. IRS binds to the receptor.
- already a dimer
- needs signal to bind to activate tyrosine kinase activity
- example of PI3 kinase signaling
Draw and describe the two different signaling pathways initiated by activation of the insulin receptor (MAP kinase and PI3 kinase)
After insulin activates alpha receptor and IRS attaches either Grb2 or PI3-kinase attach: Grb2 binds with GAP1 PIP and activates Ras/MAP kinase pathway, which is the same cascade as the EGF PI3-Kinase PIP
(a) The activation of PI-3-kinase leads to the generation of phosphatidylinositol 3,4,5- trisphosphate, which is a membrane-binding site or proteins with pleckstrin homology domains, such as PDK1 and PK B
(b) the activation of PK B (Akt) promotes cell survival (antiapoptotic), as well as propagating some specific insulin effects
Provide a general overview of the following kinase receptors: serine-threonine kinase
Receptor serine-threonine kinase
- Heterodimerizes after signal binding
- Serine kinase activity poised
Provide a general overview of the following kinase receptors: Cytokine Receptors
Cytokine Receptors
- Receptor kinases have no intrinsic kinase activity
- JAK binding provides tyrosine kinases activity
- Example of direct signaling to nucleus (STATs)
