Corticotropin-releasing hormone excites adrenocorticotropin-secreting human pituitary adenoma cells by activating a nonselective cation current

Abstract

The mechanisms of corticotropin-releasing hormone (CRH)-induced excitation of ACTH-secreting adenoma cells were investigated using the perforated whole-cell clamp technique and intracellular Ca2+ concentration ([Ca2+](i)) measurement. CRH depolarized ACTH-secreting adenoma cells by activating a nonselective cation current that showed slight inward rectification. This channel did not seem to be a member of the Ca2+- activated cation currents because it was activated even when the [Ca2+](i) was chelated below 50 nM. The activation of the current was induced by protein kinase A-mediated pathways. By [Ca2+](i) measurement, CRH increased [Ca2+](i) of these cells dependently on voltage-gated Ca2+ current. This CRH-induced [Ca2+](i) increase was abolished in Na+-free extracellular solution, but was not abolished by the addition of 5 μM tetrodotoxin to the extracellular solution. CRH-induced ACTH secretion from the cultured adenoma cells was also abolished in Na+-free extracellular solution, but not in tetrodotoxin-containing extracellular solution. These data indicate that a Na+ current (maybe the nonselective cation current) other than voltage- gated Na+ current plays an important role in CRH-induced [Ca2+](i) increase and ACTH secretion. CRH also activated a nonselective cation current in nonadenoma human corticotrophs, suggesting that the activation of a nonselective cation current is a physiological mechanism of CRH-induced excitation in human corticotrophs.