Abstract
Erythropoietin-producing human hepatocellular receptor (EPH) B6 (EPHB6) is a member of the receptor tyrosine kinase family. We previously demonstrated that EPHB6 knockout reduces catecholamine secretion in male but not female mice, and castration reverses this phenotype. We showed here that male EPHB6 knockout adrenal gland chromaffin cells presented reduced acetylcholine-triggered Ca2+ influx. Such reduction depended on the non-genomic effect of testosterone. Increased large conductance calcium-activated potassium channel current densities were recorded in adrenal gland chromaffin cells from male EPHB6 knockout mice but not from castrated knockout or female knockout mice. Blocking of the large conductance calcium-activated potassium channel in adrenal gland chromaffin cells from male knockout mice corrected their reduced Ca2+ influx. We conclude that the absence of EPHB6 and the presence of testosterone would lead to augmented large conductance calcium-activated potassium channel currents, which limit voltage-gated calcium channel opening in adrenal gland chromaffin cells. Consequently, acetylcholine-triggered Ca2+ influx is reduced, leading to lower catecholamine release in adrenal gland chromaffin cells from male knockout mice. This explains the reduced resting-state blood catecholamine levels, and hence the blood pressure, in male but not female EPHB6 knock mice. These findings have certain clinical implications.
Highlights
Erythropoietin-producing hepatocellular receptors (EPHs), the largest family of receptor tyrosine kinases, comprise about 25 percent of known receptor tyrosine kinases[1]
The present study revealed that EPHB6 deletion decreased male but not female adrenal gland chromaffin cell Ca2+ influx and catecholamine secretion
Testosterone was required for this phenotype, as the absence of both EPHB6 and testosterone reversed the KO adrenal gland chromaffin cell phenotype to that of their wild type (WT) controls
Summary
Erythropoietin-producing hepatocellular receptors (EPHs), the largest family of receptor tyrosine kinases, comprise about 25 percent of known receptor tyrosine kinases[1]. EPHBs and EFNBs are a novel yin and yang system that finely tunes blood pressure homeostasis In all such cases, sex hormones act in concert with these EPHs/EFNs for blood pressure regulation. Male EPHB6 knockout (KO) mice have reduced blood catecholamine levels in a resting state[16], which counteracts the outcome of increased vascular smooth muscle cell contractility, resulting in normal blood pressure. This, concomitantly with enhanced vascular smooth muscle cell contractility, results in blood pressure elevation in these castrated KO mice. This body of evidence indicates that EPHB6 and male sex hormones are acting in concert to regulate catecholamine secretion and blood pressure. We further demonstrated that Ca2+ influx decrease was the consequence of enhanced large conductance calcium-activated potassium (BK) currents in these cells
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