Corticotropin-releasing hormone excites adrenocorticotropin-secreting human pituitary adenoma cells by activating a nonselective cation current.
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 Ca(2+)-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 microM 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.
Fourth Department of Internal Medicine, University of Tokyo School of Medicine, Bunkyo-ku, Japan.
K
K
Takano
J
J
Yasufuku-Takano
A
A
Teramoto
T
T
Fujita
D000236:Adenoma / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D002118:Calcium / Q000502:physiology; D002412:Cations; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004553:Electric Conductivity; D006801:Humans; D015640:Ion Channel Gating; D008564:Membrane Potentials; D010903:Pituitary Gland, Anterior / Q000378:metabolism*; D010911:Pituitary Neoplasms / Q000378:metabolism*; D015398:Signal Transduction; D012964:Sodium / Q000502:physiology
D002412:Cations; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D012964:Sodium; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium