FML aka cAMP and tyrosine kinase receptor pathways

cAMP signaling (second messengers in water-soluble hormones) works in the specific order: 1) Water-soluble hormones binds to the receptor (present through both sides of the membrane, changing structure of the receptor) , 2) Receptor activates the Gs-protein (Gs-protein present along the inner membrane surface, discards normally present GDP for free-floating GTP), 3) Gs-protein activates adenylate cyclase (otherwise inactive membrane protein), 4) The activated adenylate cyclase generates cAMP (cyclic AMP, by binding ATP that had been free-floating within the cell), and 5) cAMP activates the inactive protein kinases (present free-floating within the cell). The activated protein kinases phosphorylate many proteins within the cell (via activation of some and deactivation of others), thus changing their activity and then changing the cell’s response when exposed to the hormone. Deactivation of the cAMP begins once the hormone is no longer bound to the receptor. The GTP on the Gs-protein (still hooked up with the adenylate cyclase) is converted into GDP, thus deactivating the G-protein. At this point, G-protein and adenylate cyclase break apart and adenylate cyclase becomes inactive again, thus producing no more cAMP from the ATP. Existing free-floating cAMP present within the cell are degraded by the enzyme phosphodiesterase (free-floating within the cell as well) into AMP. Protein kinases then inactivate with the lack of cAMP, thus preventing further phosphorylation. We are now back to baseline at this point. Some important things to note is that the hormone is the first messenger and the cAMP is the second messenger. The initial receptors are determined by their ability to activate the Gs-protein or are involved with protein kinase activity. The phosphorylation activity of the protein kinases can include affecting ion channels in the membrane. G-proteins, like the ones we went through are stimulatory, but there are also inhibitory G-proteins that inhibit production of cAMP and the subsequent response of the cell. Another type of G-protein activates an intracellular messenger system that uses diacylglycerol and inositol triphosphate as second messengers. When a hormone binds to the receptor, the receptor changes shape and activates the G-protein, like normal. GDP is released from the G-protein and GTP is bound, like normal. The activated G-protein travels along the membrane to activate a membrane enzyme, phospholipase C. The activated phospholipase C then attaches to phosphatidylinositol bisphosphate (PIP2), membrane phospholipid, to cleave into diacylglycerol (DAG) and inositol triphosphate (IP3). Both of these act as second messengers: DAG remains in the membrane where it activates protein kinase C, while IP3 enters the cytosol. The activated protein kinase C phosphorylates other proteins causing responses of the cell, like normal. IP3 prompts the endoplasmic reticulum (ER) to release calcium ions (Ca2+) which then also behave like second messengers. Ca2+ can act directly on proteins or bind to the protein calmodulin that can act on proteins to cause the response of the cell. Another type of plasma membrane receptor utilizes protein kinase activity for its effect (ie- hormones that bind to tyrosine kinase receptors). When a hormone binds to the tyrosine kinase receptor (present across the membrane), the receptor connects to the neighboring tyrosine kinase receptor.  Once these have connected, the structures change shape, such that they are able to phosphorylate tyrosine groups for each other (autophosphorylation, but only when the receptors are of the same type). The phosphorylated tyrosine groups provide docking sites where relay proteins bind, which indicates a series of protein phosphorylation’s that lead to the response of the cell. Receptors with tyrosine kinase activity often bind hormones like insulin and other growth factors that affect cell growth and differentiation.