Soluble adenylyl cyclase (sAC) regulates calcium signaling in the vascular endothelium

Abstract

The vascular endothelium acts as a selective barrier between the bloodstream and extravascular tissues. Intracellular [Ca 2+ ] i signaling is essential for vasoactive agonist-induced stimulation of endothelial cells (ECs), typically including Ca 2+ release from the endoplasmic reticulum (ER). Although it is known that interactions of Ca 2+ and cAMP as ubiquitous messengers are involved in this process, the individual contribution of cAMP-generating adenylyl cyclases (ACs), including the only soluble AC (sAC; ADCY10), remains less clear. Using life-cell microscopy and plate reader-based [Ca 2+ ] i measurements, we found that human immortalized ECs, primary aortic and cardiac microvascular ECs, and primary vascular smooth muscle cells treated with sAC-specific inhibitor KH7 or anti-sAC-small interfering RNA did not show endogenous or exogenous ATP-induced [Ca 2+ ] i elevation. Of note, a transmembrane AC (tmAC) inhibitor did not prevent ATP-induced [Ca 2+ ] i elevation in ECs. Moreover, Lphenylephrine-dependent constriction of ex vivo mouse aortic ring segments was also reduced by KH7. Analysis of the inositol-1,4,5-trisphosphate (IP 3 ) pathway revealed reduced IP 3 receptor phosphorylation after KH7 application, which also prevented [Ca 2+ ] i elevation induced by IP 3 receptor agonist adenophostin A. Our results suggest that sAC rather than tmAC controls the agonist-induced ER-dependent Ca 2+ response in ECs and may represent a treatment target in arterial hypertension and heart failure.

Piezo1 induces endothelial responses to shear stress via soluble adenylyl Cyclase-IP3R2 circuit

“… 53 , 54 sAC tethered to the mitochondria and microtubules 58 can generate cAMP in close proximity to IP 3 R2, which localizes at ER-mitochondrial interaction sites. 59 Therefore, the subcellular organization of cAMP signals 60 , 61 distinguishes the functional role of sAC from the transmembrane AC1, AC3, and AC8 isoforms that are also activated by Ca 2+ signaling through binding to calmodulin. 62 …”

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.…”

cAMP: A master regulator of cadherin‐mediated binding in endothelium, epithelium and myocardium

“…While the cAMP localized at the plasma membrane strengthens barrier function, the cytosolic pool of cAMP was reported to cause barrier dysfunction. 13,82,83,84,85,86,87 In this line of thoughts, a number of reviews discussed the existence of signalosome complexes where a unique combination of cyclic nucleotide effectors such as PKA or other kinases, phosphatases, ACs and Epac are in interaction with PDE and/or other scaffolding proteins (i.e. AKAPs, βarrestin, or RACK1) to promote highly compartmentalized cyclic nucleotide signaling platforms.…”