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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