Abstract
The erythropoietin-producing human hepatocellular receptor EPH receptor B6 (EPHB6) is a receptor tyrosine kinase that has been shown previously to control catecholamine synthesis in the adrenal gland chromaffin cells (AGCCs) in a testosterone-dependent fashion. EPHB6 also has a role in regulating blood pressure, but several facets of this regulation remain unclear. Using amperometry recordings, we now found that catecholamine secretion by AGCCs is compromised in the absence of EPHB6. AGCCs from male knockout (KO) mice displayed reduced cortical F-actin disassembly, accompanied by decreased catecholamine secretion through exocytosis. This phenotype was not observed in AGCCs from female KO mice, suggesting that testosterone, but not estrogen, contributes to this phenotype. Of note, reverse signaling from EPHB6 to ephrin B1 (EFNB1) and a 7-amino acid-long segment in the EFNB1 intracellular tail were essential for the regulation of catecholamine secretion. Further downstream, the Ras homolog family member A (RHOA) and FYN proto-oncogene Src family tyrosine kinase (FYN)-proto-oncogene c-ABL-microtubule-associated monooxygenase calponin and LIM domain containing 1 (MICAL-1) pathways mediated the signaling from EFNB1 to the defective F-actin disassembly. We discuss the implications of EPHB6's effect on catecholamine exocytosis and secretion for blood pressure regulation.
Highlights
The erythropoietin-producing human hepatocellular receptor Erythropoietin-producing human hepatocellular receptors (EPH) receptor B6 (EPHB6) is a receptor tyrosine kinase that has been shown previously to control catecholamine synthesis in the adrenal gland chromaffin cells (AGCCs) in a testosteronedependent fashion
We demonstrated that EPH receptor B6 (EPHB6) reverse signaling via a 7-aa intracellular sequence of EFNB1 between aa 322 and 328 was critical for regulating CAT exocytosis in AGCCs
The signaling from EFNB1 traversing through Ras homolog family member A (RHOA) as well as through the family tyrosine kinase (FYN)/c-ABL/MICAL-1/filamentous actin (F-actin) pathways was necessary for EPHB6’s effect on CAT secretion
Summary
The erythropoietin-producing human hepatocellular receptor EPH receptor B6 (EPHB6) is a receptor tyrosine kinase that has been shown previously to control catecholamine synthesis in the adrenal gland chromaffin cells (AGCCs) in a testosteronedependent fashion. When AGCCs from female KO mice were treated shortly for 15 min with cell-impermeable BSA-conjugated testosterone, their F-actin disassembly was compromised (Fig. 2E). When AGCCs from male WT mice were treated with RHOA inhibitor Rhosin, no effect on F-actin disassembly was observed (Fig. 3F).
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