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Calmodulin is an Intracellular Ca2.docx

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Physiology 3140A
Donglin Bai

Calmodulin is an Intracellular Ca Receptor 2+ 2+ 6  Since concentration of free Ca in cytosol doesn’t go above 6 x 10 M when cell is activated  proteins in the cell that are Ca receptors or that are altered by increases in cytosolic Ca must have high affinity for the binding of Ca (K approx. 10 M) -6 2+ a -3 2+  Concentration of free Mg in cytoplasm is about 10 M thus Ca binding sites must have selectivity for Ca compared to Mg of at least 1000-fold  Receptors must have high affinity & selectivity  Calmodulin is an abundant Ca binding protein found in all eukaryotic cells which functions as a multi- 2+ 2+ purpose intracellular Ca receptor mediating many Ca related processes  Allosteric activation of Calmodulin by Ca is analogous to allosteric activation of PKA by cAMP but Ca /calmodulin has no intrinsic enzyme activity itself but acts by binding to other proteins  In some cases, calmodulin is a permanent regulatory subunit of an enzyme  In most causes binding of Ca enables calmodulin to bind to various target proteins thereby altering their activity  Alternation of function of cellular proteins by Ca & calmodulin: 2+  Targets regulated by Ca /calmodulin include various enzymes & membrane transporters  Most of the actions of Ca in the cell are mediated by Ca /calmodulin-dependent proteins  Although some CaM-kinases have very specific functions & narrow substrate specificities (ex. myosin light-chain kinase & phosphorylase kinase) – others have broader substrate specificities and are called multifunctional CaM-kinases (ex. CaM-kinase II) 2+  CaM-kinase II is switched to activated state when exposed to Ca /calmodulin & remains activated even after cytosolic Ca levels return to normal  This memory is due to the fact that CaM-kinase II has phosphorylated itself as well as phosphorylated other substrate proteins  Autophosphorylation prolongs duration of activation of the kinase beyond the duration of the 2+ activating Ca signal  Important in cellular functions: learning & memory in vertebrae nervous system Lipid-Derived Chemical Mediators II Introduction • Lipids or lipid-derived productions in signal transduction o Generated by actions of phospholipase acting on membrane phospholipids, most often PC & Π o Implicated as mediators & second messengers in signal transduction o Best characterized example: generation of inositol triphosphate (3P ) & diacylglycerol through actions of phospholipase C-β on phosphatidylinositol o Other classes of lipid mediators have also been described by inter- and intracellular signaling molecules, including products derived from enzymatic breakdown of phosphatidylcholine & sphingolipids & mediators that can serve both autocrine & endocrine functions such as prostaglandins and platelet-activating factor Elcosanoids (including Prostaglandins) • Large group of compounds including prostaglandins (reproduction system), thromboxanes (control of smooth mu
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