title: Arginine Vasopressin Potentiates the Stimulatory Action of CRH on Pituitary Corticotropes via a Protein Kinase C-Dependent Reduction of the Background TREK-1 Current.
abstract: The hypothalamic hormone arginine vasopressin (AVP) potentiates the stimulatory action of CRH on ACTH secretion from pituitary corticotropes, but the underlying mechanism is elusive. Using the perforated patch-clamp technique to monitor membrane potentials in mouse corticotropes, we found that AVP triggered a transient hyperpolarization that was followed by a sustained depolarization. The hyperpolarization was caused by intracellular Ca(2+) release that in turn activated the small conductance Ca(2+)-activated K(+) (SK) channels. The depolarization was due to the suppression of background TWIK-related K(+) (TREK)-1 channels. Direct activation of protein kinase C (PKC) reduced the TREK-1 current, whereas PKC inhibition attenuated the AVP-mediated reduction of the TREK-1 current, implicating the involvement of PKC. The addition of CRH (which stimulates the protein kinase A pathway) in the presence of AVP, or vice versa, resulted in further suppression of the TREK-1 current. In corticotropes with buffered cytosolic Ca(2+) concentration ([Ca(2+)]i), AVP evoked a sustained depolarization, and the coapplication of AVP and CRH caused a larger depolarization than that evoked by AVP or CRH alone. In cells with minimal perturbation of [Ca(2+)]i and background TREK-1 channels, CRH evoked a sustained depolarization that was superimposed with action potentials, and the subsequent coapplication of AVP and CRH triggered a transient hyperpolarization that was followed by a larger depolarization. In summary, AVP and CRH have additive effects on the suppression of the TREK-1 current, resulting in a more robust depolarization in corticotropes. We suggest that this mechanism contributes to the potentiating action of AVP on CRH-evoked ACTH secretion.
authors.affiliation: Department of Pharmacology, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
authors.forename: Andy K
authors.initials: AK
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Tse
authors.affiliation: Department of Pharmacology, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
authors.forename: Amy
authors.initials: A
authors.lastname: Tse
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D052680:Corticotrophs / Q000378:metabolism / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D004357:Drug Synergism; D008564:Membrane Potentials / Q000187:drug effects; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques; D024683:Potassium Channels, Tandem Pore Domain / Q000378:metabolism / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism*
chemical_list: D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1; D001127:Arginine Vasopressin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D011493:Protein Kinase C; D002118:Calcium