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 × 10−8 M) and the selective NPR-C agonist, cANF (2 × 10−8 M), significantly inhibit L-type Ca2+ current ( ICa(L)) by ∼50%. This effect on ICa(L) is mimicked by dialyzing a Gi-activator peptide (10−7 M) into these cells, implicating a role for the inhibitory G protein, Gi. These NPR-C–mediated effects were specific to ICa(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 (∼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 ICa(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.
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