![]() ![]() Regulation of transcription by PKA is mainly achieved by direct phosphorylation of the transcription factors cAMP-response element-binding protein (CREB), cAMP-responsive modulator (CREM), and ATF1. In addition, it regulates the expression and activity of various ACs and PDEs. PKA also decreases the activities of Raf and Rho and modulates ion channel permeability. In contrast, it activates MAP kinases in this case, PKA promotes phosphorylation and dissociation of an inhibitory tyrosine phosphatase (PTP). For example, it phosphorylates and thereby inactivates phospholipase C (PLC) β2. PKA also regulates other signaling pathways. PKA phosphorylates numerous metabolic enzymes, including glycogen synthase and phosphorylase kinase, which inhibits glycogen synthesis and promotes glycogen breakdown, respectively, and acetyl CoA carboxylase, which inhibits lipid synthesis. ![]() ![]() They can also target it to particular subcellular locations and anchor it to ACs (for immediate local activation of PKA) or PDEs (to create local negative feedback loops for signal termination) ( Wong and Scott 2004).Ī large number of cytosolic and nuclear proteins have been identified as substrates for PKA ( Tasken et al. PKA-anchoring proteins (AKAPs) provide specificity in cAMP signal transduction by placing PKA close to specific effectors and substrates. The catalytic activity of the C subunit is decreased by a protein kinase inhibitor (PKI), which can also act as a chaperone and promote nuclear export of the C subunit, thereby decreasing nuclear functions of PKA. It is activated by the binding of cAMP to two sites on each of the R subunits, which causes their dissociation from the C subunits ( Taylor et al. Protein kinase (PKA), the best-understood target, is a symmetrical complex of two regulatory (R) subunits and two catalytic (C) subunits (there are several isoforms of both subunits). There are three main effectors of cAMP: PKA, the guanine-nucleotide-exchange factor (GEF) EPAC and cyclic-nucleotide-gated ion channels. Crosstalk with other pathways provides further modulation of the signal strength and cell-type specificity, and feedforward signaling by PKA itself stimulates PDE4. 2), such as calcium signaling (through calmodulin, CamKII, CamKIV, and calcineurin ), subunits of other G proteins (e.g., α i, α o, and α q proteins, and the βγ subunits in some cases), inositol lipids (by PKC), and receptor tyrosine kinases (through the ERK MAP kinase and PKB) ( Yoshimasa et al. Indeed both ACs and PDEs are regulated positively and negatively by numerous other signaling pathways (see Fig. 2002).Īlternatively, AC activity can be inhibited by ligands that stimulate GPCRs coupled to G i and/or cAMP can be degraded by PDEs. cAMP generated as a consequence of AC activation can activate several effectors, the most well studied of which is cAMP-dependent protein kinase (PKA) ( Pierce et al. The βγ subunits can also stimulate some AC isoforms. α s is released from heterotrimeric αβγ G-protein complexes following binding of agonist ligands to GPCRs (e.g., epinephrine in the case of β adrenoceptors) and binds to and activates AC. Most ACs (soluble bicarbonate-regulated ACs are the exception) are activated downstream from G-protein-coupled receptors (GPCRs) such as the β adrenoceptor by interactions with the α subunit of the G s protein (α s). ![]()
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