Principal role of adenylyl cyclase 6 in K+ channel regulation and vasodilator signalling in vascular smooth muscle cells

Abstract

AimsMembrane potential is a key determinant of vascular tone and many vasodilators act through the modulation of ion channel currents [e.g. the ATP-sensitive potassium channel (KATP)] involved in setting the membrane potential. Adenylyl cyclase (AC) isoenzymes are potentially important intermediaries in such vasodilator signalling pathways. Vascular smooth muscle cells (VSMCs) express multiple AC isoenzymes, but the reason for such redundancy is unknown. We investigated which of these isoenzymes are involved in vasodilator signalling and regulation of vascular ion channels important in modulating membrane potential.Methods and resultsAC isoenzymes were selectively depleted (by >75%) by transfection of cultured VSMCs with selective short interfering RNA sequences. AC6 was the predominant isoenzyme involved in vasodilator-mediated cAMP accumulation in VSMCs, accounting for ∼60% of the total response to β-adrenoceptor (β-AR) stimulation. AC3 played a minor role in β-AR signalling, whereas AC5 made no significant contribution. AC6 was also the principal isoenzyme involved in β-AR-mediated protein kinase A (PKA) signalling (determined using the fluorescent biosensor for PKA activity, AKAR3) and the substantial β-AR/PKA-dependent enhancement of KATP current. KATP current was shown to play a vital role in setting the resting membrane potential and in mediating the hyperpolarization observed upon β-AR stimulation.ConclusionAC6, but not the closely related AC5, plays a principal role in vasodilator signalling and regulation of the membrane potential in VSMCs. These findings identify AC6 as a vital component in the vasodilatory apparatus central to the control of blood pressure.

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

“…K ATP channels have been implicated in the mechanism of action of vasodilators that are thought to act through the cAMP-signaling cascade such as adenosine (24, 308, 664, 761, 1193), PGI 2 (161, 664), PGE 1 (378), PGE 2 (161), CGRP (759, 1072, 1184, 1520), vasoactive intestinal peptide (1257, 1592), and agonists of β-adrenergic receptors (664, 1005, 1048, 1068) (Fig. 8).…”

“…8). This involves receptor-mediated activation of adenylate cyclase type 6 [AC6 (1068)], formation of cAMP and activation of PKA, which is targeted to the channels by AKAPs (569), with the channels localized in caveolae (1250). Exogenous caveolin-1 inhibits K ATP channel activity suggesting that localization in caveolae is also important in regulation of the channel’s basal activity (313).…”

Hydrogen Sulfide and Urogenital Tract

“…K ATP channels may also act by increasing cyclic adenosine monophosphate (cAMP) and thus cause relaxation. In fact, K ATP channels are a physiologically important target of the adenylate cyclase/cAMP/ PKA signaling pathway (Nelson et al 2011), confirming indirectly the possible involvement of this channel as proposed by Srilatha et al in 2007. In fact, the effect of NaHS in rabbit CC can be blocked by using MDL 12,330A, an adenylate cyclase inhibitor (Srilatha et al 2007). On this basis, it is feasible to hypothesize that in diabetes, where there is a reduced activity of these channels, the H 2 S pathways may be involved in ED associated with the diabetes.…”

Gene expression and DNA methylation analyses suggest that immune process‐related ADCY6 is a prognostic factor of luminal‐like breast cancer

“…31 Studies have shown that different subtypes of AC have different associations with various diseases, and there is a nonspecific cross-coordination or antagonistic effect between the effect of each subtype effect. 32,33 Nonselective activation/inhibition contributes to many potential adverse reactions. 34,35 Therefore, the regulation of cAMP by selective activation or by the inhibition of various AC subtypes in different tissues is a key research area for the development of new drugs that target AC.…”