Activation of PKA and Epac proteins by cyclic AMP depletes intracellular calcium stores and reduces calcium availability for vasoconstriction

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

“…Taken to-gether, these results suggest that the physiological function of EPAC on potassium current is more likely related to BK Ca channel activation, additive with the action of PKA on K ATP , promoting hyperpolarized cells and a relaxed vascular state. In support of the relaxant function of EPAC and PKA, in a Ca 2ϩ -free extracellular environment, both EPAC and PKA activation are also observed to slowly leak cytosolic Ca 2ϩ from the SR reducing the SR load and attenuating contraction (208).…”

“…Although multiple groups agree that EPAC activation modulates the Ca 2ϩ transient, the direction of modulation is still debated (778,779,819,820). For example, in contrast to the results mentioned above, 007 activation of EPAC signaling reduced SR Ca 2ϩ load correlating with decreased Ca 2ϩ transients (154,208,820). Ergo, the level of Ca 2ϩ sparks were measured to simulate spontaneous Ca 2ϩ released from the SR by RyR activation which alter the magnitude of Ca 2ϩ released during electrical stimulation.…”

“…Briefly, cAMP acts as a relaxant for vascular smooth muscles through inhibition of the contractile forces generated by RhoA. Downstream cAMP effectors PKA and EPAC are implicated in the attenuation of RhoA-mediated contractile force in smooth muscles by a number of mechanisms including inhibitory phosphorylation of RhoA, disruption of SR calcium induction, or calcium desensitization of MYPT1 and subsequent activation of MLCP (208,272,749,1125,1133). In support of these actions by EPAC, the antagonistic modulation of RhoA activity by EPAC activation is lost in Rap1B-null animals (1213).…”

“…Also, as noted in the above subsection on Ca 2ϩ handling, EPAC is implicated in the regulation of cytosolic Ca 2ϩ levels in cardiomyocytes. Interestingly, during relaxation of vascular smooth muscles, EPAC activation is implicated in reduction of cytosolic Ca 2ϩ by increasing BK Ca channels activity (878) or slowly leaking cytosolic Ca 2ϩ from the SR to reduce the SR load (208), consequently hyperpolarizing the membrane and attenuating contractile states, respectively. EPAC activation is also associated with the activation of eNOS, along with PKA, in endothelial cells to produce NO and induce relaxation of nearby muscle (336,878).…”

G protein-coupled receptor signaling regulates ER-mitochondria contacts

“…Given the weaker effect of chemical inhibitors of PLC than that of Gaq, we postulate that the isoproterenol-induced cytosolic Ca 2+ increase could be mediated not only by a direct activation of PLC/IP3, but possibly through an unknown pathway under b-AR/Gaq or through a crosstalk with Gas/cAMP/EPAC pathway. In this regard, it is interesting to note that a recent study showed EPAC agonist, 8-CPT-cAMP, promoted intracellular Ca 2+ release, which was not through IP3 receptor, from sarcoplasmic reticulum (70).…”