IPHY 4440 1st Edition Lecture 8 Outline of Current Lecture I.Dimer formationII. How does occupied receptor bring about change in a target cell?III. Application of epinephrineIV. Amplification systemV. Metabolism of 2nd messengerVI. Shutting the system downVII. Membrane receptor typesCurrent LectureI. Dimer formation Occupied receptors often form dimers (after they bind)2 kinds: activity levels may differ1) Homodimers: hooks up with another receptor that looks just like it 2) Heterodimers: looks similar but different II. How does occupied receptor bring about change in a target cell?If cannot open/close ion channels, function as an enzyme, function as a transcriptionfactor then must activate a second messenger.. GCPRs do this- and can now increase enzyme or ion channels or act on transcription factors A) Second messenger pathway:Bioregulator (1st messenger)  occupied receptor  activate effector protein = signal generating protein (different than R)  second messenger  effect- The signal-generating protein acts directly on some sort of substrate III. Application of epinephrineE increases blood glucose, lipid breakdown, and the contractile force of heart all meditated by cAMPMechanism: liver  E binds to B-adrenergic receptor (GPCR)  activates enzyme system  glycogen  glucose phosphate - GPCR relies on a second messenger How does this activation occur? These notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.- Forms a complex with E bound to receptor complex and activates the enzyme (AC) adenylyl cyclase = signal generating protein (makes second messengers) - AC mediates the conversion from ATP  cAMP  activates protein kinase A (PKA)  phosphorylates other proteins depending on the tissue - Phosphorylase b is biologically inactive - Phosphorylase a is active to breakdown glucose to glucose-phosphate IV. Amplification system1st messenger  2nd messenger  protein kinase  (+) enzyme  tons of effects- it is a cascade of events and second messengers that have the ability to amplify their biological effects- Amplify effects with every step – very flexible - This system is why hormones can exist at such low levels but create so many biological effects - Second messengers can produce different effects depending on the tissue and the enzymes available- Ex: cAMP in the adipose tissue activates PKA that is either a hormone-dependentlipase or induce lipolysis (breakdown of fats) - Ex: cAMP in cardiac muscle activates PKA which opens calcium channel (keeps them more open and for longer) to create stronger and more sustained contractions V. Metabolism of 2nd messengerA. Phosphodiesterase (PDE): one PDE specific for cAMP and breaks down cAMP - Inhibited by methyl xanthines, caffeine, theophyllineB. IP3 and DAG: cruicial second messengers (just as versatile and powerful as cAMP)Key: memorize the diagram very well on slide 20 VI. Shutting the system downA. Inactivation of ligand= degrading enzyme in cell membrane and in extracellular fluids - Bio regulators do not persist for a very long time- Enzymes have more specific purposes that make sure they don’t stay around for too long B. Reuptake of ligand by secreting cell - Works for neuromodulators, neurotransmitters, paracrine/autocrine but not hormones..why?- Because hormones end up in the blood, as soon as secreted it is quickly transported and Neurocrines are released into synapse so easy to take back upC. Internalization of occupied receptors- Clathrin-coated pits: patch of membrane- Induce endocytosis (endosomes) and fuse with lysosomes called endolysosomes (break down stuff in vesicles) - Another way to shut down the system - Can also degrade or recycle - Goal of internalized receptors are to destroy VII. Membrane receptor typesA. G-protein coupled receptors (bind GTP to GDP)- All G-proteins have 3 subunits: alpha, beta, gamma B. Receptors with inherent enzyme activity C. Receptors that are ion channels (mostly neurotransmitter receptors)How is Gs (stimulatory G-protein) activated? - Inactive state (gamma-beta-alpha-GDP)- Active state gamma-beta dissociates from