Hormones, Receptors, and Rhythms PDF

Section 1 Hormones Receptors and Rhythms Part 2 Response of a cell to a signal for that cell to survive, need to be stimulated by 3 signals (not necessarily 3, but just to show that’s multiple signals) D and E says: survive + divide vThe fate of a cell response depends on a multitude of extracellula...

Section 1 Hormones Receptors and Rhythms Part 2 Response of a cell to a signal for that cell to survive, need to be stimulated by 3 signals (not necessarily 3, but just to show that’s multiple signals) D and E says: survive + divide vThe fate of a cell response depends on a multitude of extracellular signals. F and G: survive + differentiate instead of dividing vMost cells undergo programmed death if signals are absent especially survival signals not always pathological, part of physiological development too Life: RBC: 120 days Skin: 3 to 8 days Intestinal epithelial: 1 day Response of a cell to a signal always protein vRecognition of signal by receptor ligand = hormones signal mediators vChange of intracellular network of proteins vActivation of target genes or proteins vCellular response Hormone Action can have exponential amplification of the signal: level 1 mediator activates level 2 mediator, etc. vOften the signal is exponentially amplified during transmission and results in an on or off stage vOne or more of the signaling proteins interact with target proteins (i.e., key regulatory proteins that determine the properties of a cell) vThe modified target proteins alter the properties of the cell vAlso triggers a feedback circuit that shuts off the receptor or removes it from the cell surface negative feedback Hormone Action Signals need to come outside of the cell Based on the signal receptor pathways can be divided into two main classes: vPathways with cell-surface receptors vPathways with intracellular receptors bc can diffuse through the lipid bilayer (membrane) Rules and Exceptions! vHydrophilic hormones have cell surface receptors and hydrophobic hormones have intracellular receptors vLipid hormones, prostaglandins and leukotrienes have cell surface receptors vMany steroids and bile acids have both intracellular and cell surface receptors vRecent development: many metabolites have receptors and thus can can be used as signalling molecule bc they have receptors + fuel for function as hormones nutrients energy Metabolite Receptor Lactate GPR81 Ketone bodies (BHB) FFAR3/HCAR2 Succinate GPR109B ⍺-ketoglutarate GPR80/99 Fatty acids GPR40/41/43/84/120 Calcium CASR Bile acids NR = nuclear receptor NR1H4/NR1I2 and TGR5 cell surface receptor intracellular receptur Basic structure of a cell surface receptor 3 domains water soluble amino acid end outside travels through lipid bilayer 20-25 a.a. needed to cross membrane once (Ala, Ile, Leu, Met, Phe, Val, Pro, Gly) lipid soluble carboxyl end vSignal binds to ectodomain vRich in cysteine residues (S-S bonds for folding). attached to CHO moieties —> complex structure where signal vOften glycosylated. aa can come in and lock in vHydrophobic transmembrane domain (alpha-helix). vCytoplasmic domain relays signal vFree ectodomain may circulate as a hormone binding protein carrier protein v The GH receptor’s ectodomain acts as a GH binding protein exception modular, can be change and can be used to study the domain The cytoplasmic domain relays the signal to the interior of the cell vThe activated cytoplasmic domain induces a signaling cascade vrelay of conformational changes of signaling proteins vSuch conformational changes are induced by vPhosphorylation of proteins vBinding between proteins Many signaling proteins are modulated by phosphorylation typically occurs on these 3 aa Serine Threonine bc they all have a polar OH which is easily exchanged by P Tyrosine Many signaling proteins are modulated by phosphorylation v Protein 1 is activated by phosphorylation v Phosphorylation can be reversed by phosphatases (resetting the switch) v Phosphorylated protein 1 acts as a kinase and phosphorylates protein 2 v Each phosphorylation step allows for signal between being activated and amplification lag deactivated depending on how time phosphatase kinase itself don’t use its own phosphate group, comes from ATP Serine or threonine vs. tyrosine phosphorylation v Phosphorylated serine and threonine more abundant than phosphorylated tyrosine (100:1) usually occurs together v Tyrosine phosphorylation often occurs at the beginning of a cascade (many receptors have or induce tyrosine kinase activity) v The phosphorylated tyrosine serves as a docking site for downstream signal proteins v The amino acid sequence that mediates docking to phosphorylated tyrosine (SH2 and SH3 domains) is conserved and diagnostic for proteins involved in the signaling cascade SH domain = assume it functions as a docking site Types of cell surface receptors vG-protein coupled receptors (GPCR) vTyrosine Kinase Receptors (RTK) vIntrinsic TK activity vRecruited TK activity vSerine-Threonine kinase receptors (RSTK) G protein-coupled receptor largest family of receptor and most targeted by drugs Second messenger 57 Protein Kinase A (PKA) A Kinase Anchoring Protein always exist as a dimer (2 copies of the same thing): 2 protein kinase A that is made up of 2 subunits: catalytic (catalyze phosphorylation step) + regulatory subunit 58 Cellular proteins regulated by cAMP-PKA Enzyme/protein Pathway/process regulated Glycogen synthase Glycogen synthesis Phosphorylase b kinase Glycogen breakdown Pyruvate kinase Glycolysis Pyruvate dehydrogenase complex Pyruvate to acetyl-CoA Hormone-sensitive lipase Triacylglycerol mobilization and fatty acid oxidation Signal control – Desensitization-Resensitization cycle bARK – b-adrenergic receptor kinase 63 work with TRH (GPCR) and added rhodamine fluorescent molecule Signal control – Desensitization Rhodamine attached to TRH normal GPCR when receptor is full: green fluorescent (lit up) Without cytoplasmic domain (need it to function —> phosphorylation) https://doi.org/10.3389/fnins.2012.00180 just appear with diffuse (whole cell looks like it’s glowing bc no phosphorylation to diminish it): how they learned that cytoplasmic domain is necessary for function Five ways in which target cells can become desensitized to a signal molecule 65 G⍺ subunits stimulates vGs⍺ alpha: Activates adenylate cyclase vGi⍺ alpha: Inhibits adenylate cyclase vGq⍺ alpha: Activates phospholipase C vIP3 and DAG and Ca signaling vGo⍺ alpha: Activates ion channels vG12/13⍺: regulate Actin cytoskeleton PLC GPCR Signaling through IP3 and Ca 69 GPCR Signaling through IP3 and Ca PIP2 = Phosphatidylinositol 4,5-bisphosphate 68 Examples of GPCRs v Hormones may use more than one G-protein v G protein use may change during development v G protein use may change depending on the hormone concentration or in different tissues