Receptor Signaling Mechanisms PDF

Receptor Signaling Mechanisms COLLIN M. CLARK, PHARMD, BCPS, BCGP CLINICAL ASSISTANT PROFESSOR [email protected] 312 PHARMACY BUILDING Objectives List and be able to describe the 5 basic mechanisms of transmembrane signaling Describe the role of G-proteins and second messengers in tran...

Receptor Signaling Mechanisms COLLIN M. CLARK, PHARMD, BCPS, BCGP CLINICAL ASSISTANT PROFESSOR [email protected] 312 PHARMACY BUILDING Objectives List and be able to describe the 5 basic mechanisms of transmembrane signaling Describe the role of G-proteins and second messengers in transmembrane signal transduction Recognize the relationships between receptor binding and the time course of drug action as it relates to signal conduction Explain mechanisms of receptor regulation  Transmembrane Signaling Mechanisms 2) Transmembrane receptor w/ 4) Ligand-gated ion channel 1) Intracellular receptor enzymatic activity 5) G-protein coupled receptors 3) Transmembrane receptor w/ bound tyrosine kinase Intracellular Receptors Requires a lipid soluble ligand Ligands include: -Corticosteroids, mineralocorticoids, sex steroids, vitamin D Exert effects by binding to a response element and regulating gene expression Intracellular Receptors Typically have a lag period of 30 minutes before effect is evident Duration of action last well beyond (hrs –days) longer than drug concentration -Dependent on turnover of proteins/enzymes Ligand-Regulated Transmembrane Enzymes and Receptor Tyrosine Kinases Phosphorylation Many of the signaling mechanisms we will discuss involve phosphorylation Involves the attachment of a phosphoryl group to a serine, threonine, or tyrosine reside Serves multiple purposes including -Amplification -Flexible regulation Ligand-Regulated Transmembrane Enzymes Receptor Tyrosine Kinases Ligand-Gated Ion Channels Drugs working on these receptors often mimic of block naturally occurring ligands -Acetylcholine, GABA, serotonin, glutamate Transmits signal across the membrane by increasing transmembrane conductance of the relevant ion and thereby altering the electrical potential across the membrane Response is rapid (millisecond scale) G-Protein Coupled Receptors G-Protein Coupled Receptors G-Protein Coupled Receptors Second Messengers Cyclic adenosine-3′,5′-monophosphate (cAMP) Phosphoinositides and Calcium Cyclic Guanosine Monophosphate Cyclic AMP (cAMP) Agonist binds GPCR which activates adenyl cyclase (AC) AC converts ATP to cAMP cAMP interacts with regulatory kinases with catalytic chains (R2C2), releasing the C chains to transfer phosphate from ATP to substrate proteins/enzymes Phosphoinositides and Calcium Some linked to GPCRs and others to receptor tyrosine kinases Phospholipase C (PLC) splits phosphatidylinositol-4,5-bisphosphate (PIP2), into two second messengers, diacylglycerol (DAG) and inositol-1,4,5- trisphosphate (IP3 or nsP3). Phosphoinositides and Calcium (continued) DAG remains in the membrane and activates protein kinase C (PK-C) to exert its effects IP3 diffuses through the cytoplasm and binds to ligand-gated Ca2+ channels on intracellular vesicles releasing Ca2+ Ca2+ will then bind the calcium binding protein calmodulin (CaM) to cause a response Cyclic Guanosine Monophosphate Only present in a few type of cells (ex retina, intestinal muscle, vascular smooth muscle In the retina, cGMP mediates vision and is destroyed by hydrolysis in response to light, mediated by a phosphodiesterase stimulated by a G protein coupled to the light- activated GPCR rhodopsin. In smooth muscle, Ligands detected by cell-surface receptors stimulate membrane- bound guanylyl cyclase to produce cGMP, and cGMP acts by stimulating a cGMP- dependent protein kinase. - The actions of cGMP in these cells are terminated by enzymatic degradation of the cyclic nucleotide and by dephosphorylation of kinase substrates. Receptor Regulation G protein-mediated responses to drugs and hormonal agonists often attenuate with time even in the continued presence of agonist Called desensitization May be rapidly reversible Can be regulated by phosphorylation and other mechanisms