C-type natriuretic peptide inhibits L-type Ca2+ current in rat magnocellular neurosecretory cells by activating the NPR-C receptor.
Magnocellular neurosecretory cells (MNCs), of the paraventricular and supraoptic nuclei of the hypothalamus, secrete the hormones vasopressin and oxytocin. As a result, they have an essential role in fundamental physiological responses including regulation of blood volume and fluid homeostasis. C-type natriuretic peptide (CNP) is present at high levels in the hypothalamus. Although CNP is known to decrease hormone secretion from MNCs, no studies have examined the role of the natriuretic peptide C receptor (NPR-C) in these neurons. In this study, whole cell recordings from acutely isolated MNCs, and MNCs in a coronal slice preparation, show that CNP (2 x 10(-8) M) and the selective NPR-C agonist, cANF (2 x 10(-8) M), significantly inhibit L-type Ca2+ current (I(Ca(L))) by approximately 50%. This effect on I(Ca(L)) is mimicked by dialyzing a G(i)-activator peptide (10(-7) M) into these cells, implicating a role for the inhibitory G protein, G(i). These NPR-C-mediated effects were specific to I(Ca(L)). T-type Ca2+ channels were unaffected by CNP. Current-clamp experiments revealed the ability of CNP, acting via the NPR-C receptor, to decrease (approximately 25%) the number of action potentials elicited during a 500 ms depolarizing stimulus. Analysis of action potential duration revealed that CNP and cANF significantly decreased 50% repolarization time (APD50) in MNCs. In summary, our findings show that CNP has a potent and selective inhibitory effect on I(Ca(L)) and on excitability in MNCs that is mediated by the NPR-C receptor. These data represent the first electrophysiological evidence of a functional role for the NPR-C receptor in the mammalian hypothalamus.
Rose
Robert A
RA
Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta T2N 4N1, Canada.
Anand-Srivastava
Madhu B
MB
Giles
Wayne R
WR
Bains
Jaideep S
JS
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007032:Hypothalamus, Anterior / Q000166:cytology*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology*; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000528:radiation effects; D009529:Nicardipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017461:Receptors, Atrial Natriuretic Factor / Q000502:physiology*
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D020098:Natriuretic Peptide, C-Type; D009320:Atrial Natriuretic Factor; D009529:Nicardipine; D000242:Cyclic AMP; D017461:Receptors, Atrial Natriuretic Factor; D002118:Calcium