Adenosine activates ATP-sensitive potassium channels in arterial myocytes via A2 receptors and cAMP-dependent protein kinase.

Abstract

The mechanism by which the endogenous vasodilator adenosine causes ATP-sensitive potassium (KATp) channels in arterial smooth muscle to open was investigated by the whole-cell patch-clamp technique. Adenosine induced voltage-independent, potassium-selective currents, which were inhibited by glibenclamide, a blocker of KATP currents. Glibenclamide-sensitive currents were also activated by the selective adenosine A2-receptor agonist 2-p-(2-carboxethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680), whereas 2-chloro-N6-cyclopentyladenosine (CCPA), a selective adenosine Al-receptor agonist, failed to induce potassium currents. Glibenclamide-sensitive currents induced by adenosine and CGS-21680 were largely reduced by blockers of the cAMP-dependent protein kinase (RpcAMP[S], H-89, protein kinase A inhibitor peptide). Therefore, we conclude that adenosine can activate KATP currents in arterial smooth muscle through the following pathway: (i) Adenosine stimulates A2 receptors, which activates adenylyl cyclase; (ii) the resulting increase in intracellular cAMP stimulates protein kinase A, which, probably through a phosphorylation step, opens KATP channels.

Critical Role of cAMP-GEFII·Rim2 Complex in Incretin-potentiated Insulin Secretion

“…Treatment of islets with antisense ODNs reduced both GLP-1-and GIPpotentiated insulin secretion, clearly indicating that the effects of the incretins are mediated in part by cAMP-GEFII. Ten M of H-89, a widely used specific inhibitor of PKA phosphorylation in intact cells (24,28,41,50), was then used to block the phosphorylation of GLUT2, a substrate of PKA in pancreatic ␤-cells (28), to evaluate incretin-potentiated insulin secretion. Interestingly, although treatment of pancreatic islets with H-89 reduced (about 50%) both GLP-1-and GIP-potentiated insulin secretions, treatment of the islets with H-89 plus antisense ODNs further reduced the insulin secretions (80 -90%), suggesting strongly that the potentiation of insulin secretion by both GLP-1 and GIP is mediated by PKA-independent as well as PKA-dependent mechanisms and that cAMP-GEFII is involved in the PKA-independent mechanism.…”

Gender-specific K+-channel contribution to adenosine-induced relaxation in coronary arterioles

“…The role of voltage-dependent K ϩ (K V ) channels in adenosine-mediated relaxation has not been reported previously; however, findings of Aiello et al (1,2) provide evidence that both protein kinase A (PKA) and isoproterenol stimulate K V channels in isolated vascular smooth muscle cells. Although controversial, adenosine has been reported to act via cAMP and PKA in vascular smooth muscle (16), providing a putative mechanism for K V -channel activation by adenosine.…”

Purinergic receptors in the splanchnic circulation

“…Indeed, it was previously observed that these A 2 receptor subtypes are expressed in the mesenteric vascular bed, although A 2B receptors are weakly expressed in comparison to A 2A receptors [71]. A 2A receptor-mediated vasodilatory effects have been observed in the rat and rabbit mesenteric artery [31,64,79,133]. These effects appear to involve the opening of potassium channels subsequent to A 2A receptor activation.…”

“…As previously referred, A 2 receptors are coupled to G s proteins, which activate adenylyl cyclase leading to an increase in intracellular cAMP. The elevation of cAMP further activates protein kinase A, which opens potassium channels probably through a phosphorylation step [79].…”