Corticotropin-releasing Hormone Activates a Nonselective Cation

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 Ca 2 1 concentration ([Ca 2 1 ] 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 Ca 2 1 -activated cation currents because it was activated even when the [Ca 2 1 ] i was chelated below 50 nM. The activation of the current was induced by protein kinase A–mediated pathways. By [Ca 2 1 ] i measurement, CRH increased [Ca 2 1 ] i of these cells dependently on voltage-gated Ca 2 1 current. This CRH-induced [Ca 2 1 ] i increase was abolished in Na 1 -free extracellular solution, but was not abolished by the addition of 5 m M tetrodotoxin to the extracellular solution. CRH-induced ACTH secretion from the cultured adenoma cells was also abolished in Na 1 -free extracellular solution, but not in tetrodotoxin-containing extracellular solution. These data indicate that a Na 1 current (maybe the nonselective cation current) other than voltagegated Na 1 current plays an important role in CRH-induced [Ca 2 1 ]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 CRHinduced excitation in human corticotrophs. ( J. Clin. Invest. 1996. 98:2033–2041.)