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Lecture 15

Biology 2290F/G Lecture 15: Functions of G Protein-Coupled Receptors in Cells

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Biology 2290F/G
Ray Zabulionis

Lecture 10: Functions of G Protein-Coupled Receptors in Cells + Activation of muscarinic acetylcholine receptor and K channels in the heart - When acetylcholine binds to its receptor, it leads to the opening of K channel and cellular hyperpolarization - Slows the rate of heart muscle contraction + - Gbeta-gamma subunit activates the effector protein (K channel) - GDP is displaced, GTP binds - The beta-gamma subunit elicits change in the effector (K channel) o This is different form most other GPCRs Regulation of Adenylyl Cyclase - Adenylyl cyclase catalyzes formation of cyclic AMP (cAMP) - GPCR/cAMP pathway is very common in many mammalian cells Major effector of GPCR is adenylyl cyclase – is a transmembrane protein - Alpha subunit can elevate or inhibit cAMP production Inappropriate activation of Adenylyl Cyclase – Cholera Toxin in intestinal epithelial cells Cholera: 200-500 000 cases/year with 20-50% mortality - Toxin enters enterocytes of small intestine using a GM1 GANGLIOSIDE RECEPTOR - Toxin maintains Galpha in astive state (GTP) - Mass activation of adenylyl cyclase - Massive increase in cAMP levels - Increase leads to hyperactivity CFTR ion channel - + - Cl pumped out and Na follows and H O loss to2intestine - Massive diarrhea The alpha subunit of the cholera toxin moves to the Galpha subunit,sbinds it and causes conformational change - Constitutively activates the Galpha protsin: bound to GTP, doesn’t hydrolyze it - This activates adenylyl cyclase, causing increased cAMP levels - Accumulates in intestinal epithelial cells, activating protein kinase A - Phosphorylates CFTR CFTR releases chloride ions into the intestinal lumen - There’s also movement of sodium through transporters, causing an accumulating of NaCl in the intestinal lumen - Movement of H O fr2m intestinal epithelial cells to lumen of small intestine, causing massive diarrhea Whooping Cough – Pertussis Toxin in Lung Epithelial Cells - Bordetella pertussis toxin enters ciliated epithelial cells in lungs - Pertussis toxin maintains Galpha subuiit in inactive state (GDP) - Mass activation of adenylyl cyclase - Mass increase in cAMP levels - Increased activity in ion pumps - Mucous secretion and electrolyte/H O acc2mulation in lungs The Galpha suiunit is turned off constitutively; can’t inhibit adenylyl cyclase - The Galpha unshecked will activate adenylyl cyclase, causing increased cAMP, phosphorylating CFTR - Salt accumulation, water accumulation due to osmotic effect - Toxin also affects cilia, which is important for moving mucous out of lungs – leads to “whooping” cough cAMP activates protein kinase A - PKA is an exception in that the catalytic domain separates from the regulatory domain - cAMP binds to the regulatory subunit in a cooperative fashion – binding the 1 cAMP to CNB-B lowers the K for binding of the decond cAMP molecule to CNB-A PKA is a trimeric complex, with 2 catalytic subunits and 2 regulatory subunits - cAMP binds to the B site first, promoting higher affinity for cAMP to the A site - when cAMP is present, it causes a conformational change in the regulatory subunit, leading to dissociation of catalytic subunits - after activation, kinases can now go and phosphorylate things - we call cAMP a second messenger: used to amplify a signal Four Common Intracellular Second Messengers Second messengers: molecules that relay signals received at receptors on cell surface 1. cAMP: activates protein kinase A (PKA) 2. cGMP: activates protein kinase G (PKG), opens cation channels in rod cells 3. DAG: activates protein kinase C (PKC) 4. IP3: opens calcium channels in the endoplasmic reticulum – calcium signalling Signal Amplification Fight-or-flight response: 2 messengers take small signals and amplify them at least 1000-fold First messengers: extracellular factors (hormones, neurotransmitters) - With each step, you get amplification of signal - Epinephrine activates adenylyl cyclase – we can have 1000-fold signal - Adenylyl cyclase catalyzes cAMP, which activates protein kinase A, which phosphorylates and activates an enzyme, which can go on to create a variety of products o Products: adrenaline rush, glucose liberation, heart muscle contraction, vasoconstriction Epinephrine is involved in the conversion of glycogen to glucose - Gluconeogenesis (synthesis of glucose from amino acids) Regulation of glycogen metabolism by cAMP Increased cAMP = increased glycogen breakdown, decreased glycogen levels - Active PKA will phosphorylate glycogen phosphorylase kinase (activating), which phosphorylates glycogen phosphorylase (activating) - This leads to the breakdown of glycogen into glucose - At the same time, active PKA ph
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