LECTURE 9 - Regulatory pathways - overview How to get...

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Regulatory pathways - overview p 503-519 How to get signals from outside the cell to the inside: -Receptors -G-protein coupled receptors -receptor tyrosine kinases Regulation of fuel metabolism: -insulin -glucagon/epinephrine Regulation of cell growth : -growth factor receptors
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Regulatory pathways - GPCRs p 503-519 GPCR = G-protein coupled receptor: -a large family of proteins -all contain 7-transmembrane helices -involved in sensing: -light -smells -Favors -hormones -chemokines (immune response) >50% of all drugs bind to GPCRs -Zyprexa for schizophrenia ($4.2 billion/yr) - antagonist for serotin receptor -Clarinex for allergies - antagonist for peripheral histidine H1 receptor -Zantac for gastric reFux and ulcers - antagonist for peripheral histidine H2 receptor -Zelnorm for irritable bowel syndrome and constipation - antagonist for peripheral 5HT4 receptor -Testosterone-analogs for fast bicycle riders - agonist for testosterone receptor
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Regulatory pathways - GPCRs p 503-519 Ligand-binding triggers conformational changes and signal is transmitted to G-proteins: agonist or antagonist
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Regulatory pathways - GPCRs p 503-519 Critical events for G-protein signaling: enhanced by GEFs (guanine nucleotide exchange factors) enhanced by GAPs (GTPase activating proteins)
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Regulatory pathways - GPCRs p 503-519 Downstream of G-proteins:
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Regulatory pathways - GPCRs p 503-519 Downstream of G α -proteins: -adenylyl cyclase -also responds to glucagon binding to glucagon receptor -concept: multiple receptors signal through a fewer number of G-proteins
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Regulatory pathways - GPCRs p 503-519 Downstream of adenylyl cyclase: -protein kinase A (aka cAMP-dependent protein kinase)
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Regulatory pathways - GPCRs p 503-519 Downstream of protein kinase A : PFK-2 -which makes F2,6-bP, regulator of PFK-1 and F1,6-bP phosphatase In the liver : want to trigger release of glucose for use by muscles, and not use it up. In muscles : different isozyme of PFK-2 is stimulated by phosphorylation, so as to promote glycolysis
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Regulatory pathways - GPCRs p 503-519 Downstream of protein kinase A : phosphorylase kinase -which activates glycogen phosphorylase -to promote glucose release -and which inactivates glycogen synthase -to stop glycogen formation
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Regulatory pathways - GPCRs p 503-519 Downstream of protein kinase A: multiple enzymes -promotes release of glucose from liver -activates glycogen phosphorylase (glycogen --> G-1-P) -inhibits burning of glucose -inactivates PFK-2 (inhibits synthesis of F2,6-diP) -activates FBPase-2 (promotes hydrolysis of F2,6-diP) -inhibit synthesis of glycogen -inactivated glycogen synthase PFK-2/ FBPase-2
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Regulatory pathways - GPCRs p 503-519 Signaling cascades -amplifcation -multiple levels oF regulation -crosstalk with other pathways
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Regulatory pathways - GPCRs p 503-519 Downstream of G βγ -proteins: -phospholipase C note, this is a lipid which is “everywhere”
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Regulatory pathways - GPCRs p 503-519 Downstream of phospholipase C: -IP 3 (1,4,5 tri-phosphate, released from lipid) and DAG
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LECTURE 9 - Regulatory pathways - overview How to get...

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