MODULE 27 PDF: Cellular Signalling

MODULE 27 Receptors that act via cAMP are coupled to a stimulatory G protein (Gs), which activates adenylyl cyclase. Inhibitory G protein (Gi), inhibits adenylyl cyclase. cAMP-dependent Protein Kinase (PKA) cAMP activates ion channels in the plasma membrane or cAMP-dependent protein kinase (...

MODULE 27 Receptors that act via cAMP are coupled to a stimulatory G protein (Gs), which activates adenylyl cyclase. Inhibitory G protein (Gi), inhibits adenylyl cyclase. cAMP-dependent Protein Kinase (PKA) cAMP activates ion channels in the plasma membrane or cAMP-dependent protein kinase (PKA). PKA transfers phosphate group from ATP to serine and threonine residues on proteins. Inactive PKA has two catalytic subunits and two regulatory subunits. cAMP binding to the regulatory subunits alters their conformation and causes their dissociation from the catalytic subunits. The released catalytic subunits are active and phosphorylate their targets. G Proteins That Activate the Inositol Phospholipid Pathway G proteins with a G alpha-q subunit activate plasma membrane-bound phospholipase C-β. The phospholipase acts on PIP2 at the inner half (leaflet) of the plasma membrane lipid bilayer. The phospholipase cleaves PIP2 to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol; at this step, the signaling pathway splits into two branches. Two Branches of the Inositol Phospholipid Pathway IP3 diffuses into the cytosol, opens Ca2+-release channels in the smooth ER membrane. The response is terminated by: 1. IP3 dephosphorylation to IP2. 2. IP3 phosphorylation to IP4. 3. Ca2+ being pumped out of the cell. Diacylglycerol (DAG) DAG remains in the plasma membrane due to its hydrophobic properties. DAG could be cleaved to arachidonic acid, a messenger and precursor of eicosanoids that participate in pain and inflammatory responses. DAG also activates the Ca2+-dependent serine/threonine protein kinase C (PKC). The rise in cytosolic Ca2+ induced by IP3 allows the translocation of PKC from the cytosol to the plasma membrane, where it is activated by Ca2+, DAG, and phosphatidylserine. Ca2+: an Intracellular Messenger Many extracellular signals increase cytosolic Ca2+. Ca2+ is low in the cytosol and high in the extracellular space and ER lumen. Low cytosolic Ca2+ is maintained by active transporters in the plasma membrane. When a signal opens Ca2+ channels, Ca2+ enters the cytosol, increasing [Ca2+] by 20-fold. Ca2+ channels: voltage-dependent; IP3-gated Ca2+-release channels releasing Ca2+ from the ER; (3) ryanodine receptors, releasing Ca2+ from the ER to stimulate muscle cell contraction or Ca2+ signaling in non-muscle cells.