Connexin Hemichannels Contribute to the Activation of cAMP Signaling Pathway and Renin Production.

Jingru Hong,Jian Yao

doi:10.3390/ijms21124462

Abstract

Connexin hemichannels play an important role in the control of cellular signaling and behaviors. Given that lowering extracellular Ca2+, a condition that activates hemichannels, is a well-characterized stimulator of renin in juxtaglomerular cells, we, therefore, tested a potential implication of hemichannels in the regulation of renin in As4.1 renin-secreting cells. Lowering extracellular Ca2+ induced hemichannel opening, which was associated with cAMP signaling pathway activation and increased renin production. Blockade of hemichannels with inhibitors or downregulation of Cxs with siRNAs abrogated the activation of cAMP pathway and the elevation of renin. Further analysis revealed that cAMP pathway activation was blocked by adenylyl cyclase inhibitor SQ 22536, suggesting an implication of adenyl cyclase. Furthermore, the participation of hemichannels in the activation of the cAMP signaling pathway was also observed in a renal tubular epithelial cell line NRK. Collectively, our results characterized the hemichannel opening as a presently unrecognized molecular event involved in low Ca2+-elicited activation of cAMP pathway and renin production. Our findings thus provide novel mechanistic insights into the low Ca2+-initiated cell responses. Given the importance of cAMP signaling pathway in the control of multiple cellular functions, our findings also highlight the importance of Cx-forming channels in various pathophysiological situations.

Highlights

The renin-angiotensin system is a major regulatory system controlling extracellular fluid volume and blood pressure
Besides heptanol, other hemichannel inhibitors, such as CBX, FFA, α and β-GA effectively inhibited low-Ca2+-initiated cAMP response element binding protein (CREB) phosphorylation (Figure 2E). These results indicate that Cx-forming hemichannels contribute to the low Ca2+-elicited activation of the cyclic adenosine monophosphate (cAMP) pathway
Using a well-characterized mouse renin-secreting cell line As4.1 cells, we characterized activation of Cx hemichannels as a key molecular event implicated in the low Ca2+-induced activation of the cAMP pathway and the induction of renin

Summary

Introduction

The renin-angiotensin system is a major regulatory system controlling extracellular fluid volume and blood pressure. Renin secretion is controlled by several factors, such as blood pressure, sodium chloride load, sympathetic nerves, hormones, cytokines, and vasoactive materials. The signal pathways underlying the actions of these factors differ, it is generally accepted that a change in intracellular Ca2+ is the common pathway through which renin secretion from JG cells is governed. Accumulated evidences indicate that Ca2+ regulates renin through modulation of adenylyl cyclase activities. Low Ca2+ enhances the activities of the Ca2+-inhibitable isoforms of adenylyl cyclases in JG cells, increasing intracellular cyclic adenosine monophosphate (cAMP) and stimulating renin synthesis [1,2,8]. Elevation in intracellular Ca2+ suppresses adenylyl cyclase and inhibits renin [5]. CAMP is a well-characterized secondary messenger in stimulation of renin synthesis and secretion [8,9,10,11]. CAMP is a well-characterized secondary messenger in stimulation of renin synthesis and secretion [8,9,10,11]. cAMP-elevating chemicals such as prostaglandins, kinins, and alpha-adrenergic agonists, all stimulate renin, whereas agents that inhibit the cAMP pathway suppress renin [11,12,13]

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Results

Conclusion