Further actions of second messengersphosphorylation cascades

The earliest known action of cAMP was as a regulator of glycogen metabolism. cAMP is now known to have diverse roles in the cell. All of its actions are mediated by activation of cAMP-dependent protein kinase, an enzyme consisting of two regulatory units and two catalytic units. Binding of two molecules of cAMP to the regulatory subunits results in the release of the two catalytic subunits, which then rapidly phosphorylate membrane or cytoplasmic proteins. As well as cAMP-dependent protein kinase, cells also contain a cGMP-dependent kinase—protein kinase C—which is activated by diacylglycerol, and various calcium-dependent kinases. These can be activated by calcium ions derived either extracellularly via L-type voltage-dependent calcium channels, or from intracellular pools as a result of the action of inositol-1,4,5-trisphosphate on the endoplasmic reticulum.

Protein kinases activated by second messengers are in general referred to as serine/threonine protein kinases, since the acceptors for phosphate in the target molecules are serine or threonine residues. In protein kinase C, cGMP-dependent kinase, and Ca 2+-calmodulin-dependent kinase, the regulatory and catalytic domains are part of the same polypeptide chain. Binding of the second messenger results in unfolding of the molecule, thus exposing and activating the catalytic region. The phosphorylation reactions mediated by these kinases may serve to integrate signals transmitted by the various second messengers. The substrates for phosphorylation in many cases include the kinase enzymes themselves. The regulatory units of cAMP-dependent protein kinase, for example, can be phosphorylated by the enzyme's catalytic units. This autophosphorylation process leads to a reduction in the rate at which the regulatory and catalytic units recombine and occurs when the cAMP concentration in the cell is low.

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