![]() ![]() ![]() Although many contemporary reviews on innate immunity focus on pathogen recognition receptors and signaling pathways ( 3), the importance of cAMP as a controller derives from its ability to exert broad modulatory effects that are independent of the pathogen, the recognition receptor, or the signaling pathway in question. This review will address cAMP regulation of innate immunity, with an emphasis on the lung. Biological processes mediated by this second messenger include memory, metabolism, gene regulation, and immune function ( 2). cAMP is now recognized as a universal regulator of cellular function in organisms including amoebas, plants, and humans ( 1). Sutherland was awarded the 1971 Nobel Prize for this work, which would prove to be the first of five Nobel Prizes recognizing research on this molecule. Sutherland during his studies of the mechanisms of hormone action. The cyclic nucleotide cyclic adenosine monophosphate (cAMP)-the original member of the family of second messengers-was discovered by Dr. Advances in Second Messenger and Phosphoprotein Res 32:1, 1998.This review will provide clinicians with an overview of the cyclic AMP axis, its role as a down-regulator of host antimicrobial defense functions, and the clinical and translational relevance of such actions. Smit MJ, Iyengar R: Mammalian adenylyl cyclases.Mons N, Decorte L, Jaffard R, Cooper DM: Ca2+-sensitive adenylyl cyclases, key integrators of cellular signalling.Houslay MD, Milligan G: Tailoring cAMP-signalling responses through isoform multiplicity.Cooper DMF, Mons N, Karpen JW: Adenylyl cyclases and the interaction between calcium and cAMP signalling.Chen Y, Cann MJ, Litvin TN, etc: Soluble adenylyl cyclase as an evolutionarily-conserved bicarbonate sensor.This drug is widely used in studies aimed at dissecting intracellular signalling pathways. It thus appears that there is tight integration between cAMP and calcium, the cell's two major internal signallers.Īll known adenylyl cyclases are stimulated by exposure of cells to the diterpene forskolin. Also, ultrastructural labelling has demonstrated a close spatial association of adenylyl cyclases with sites of calcium entry in cells. Three of these are stimulated by calcium and two are inhibited. ![]() Of potentially great significance, five of the adenylyl cyclases known are regulated by calcium. More recently, it has become clear that cyclase activity is regulated by multiple effectors, which include not the alpha subunits of G s and G i proteins, but also the beta-gamma subunits of G proteins and protein kinase C. Also, when epinephrine binds to alpha-2 adrenergic receptors, adenylyl cyclase activity is inhibited, because that receptor is coupled to via G i, an inhibitory G protein. For example, the beta-adrenergic receptor is coupled to adenylyl cyclase via G s and binding of epinephrine to this receptor leads to increased cyclic AMP synthesis. This is certainly the case in some situations. Binding of a stimulatory G alpha (G s) enhanced activity while binding of an inhibitory G alpha (G i) inhibited cyclase activity. These enzymes differ considerably in regulatory properties and are differentially expressed among tissues, adding support to observations that support a very complex model of interactions that regulate cyclic AMP production.Įarly studies indicated that cyclase activity was regulated primarily by interactions with alpha subunits of heterotrimeric G proteins, which are activated through G protein-coupled receptors. There are at least nine isoforms of adenylyl cyclase, discovered by cloning of full-length cDNAs. When adenylyl cyclase is activated, it catalyses the conversion of ATP to cyclic AMP, which leads to an increase in intracellular levels of cyclic AMP. This form of the enzyme appears to be activated by bicarbonate ion. Two catalytic domains extend as loops into the cytoplasm, as depicted in the figure to the right.Ī soluble (non-membrane bound) form of adenylyl cyclase has recently been characterized in mammalian sperm. Regulation of intracellular concentrations of cyclic AMP is largely a result in controlling adenylyl cyclase.Īdenylyl cyclases are integral membrane proteins that consist of two bundles of six transmembrane segments. Cyclic AMP functions as a second messenger to relay extracellular signals to intracellular effectors, particularly protein kinase A. Adenylyl cyclase is the enzyme that synthesizes cyclic adenosine monophosphate or cyclic AMP from adenosine triphosphate (ATP). ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |