FINAL ACCEPTED VERSION: JN-00057-2005.R2 C-type natriuretic peptide inhibits L-type Ca 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 M) and the selective NPRC agonist, cANF (2 x 10 M), significantly inhibit L-type Ca current (ICa(L)) by ~50%. This effect on ICa(L) is mimicked by dialyzing a ‘Gi-activator peptide’ (10 M) into these cells, implicating a role for the inhibitory G protein, Gi. These NPR-C mediated effects were specific to ICa(L) as T-type Ca 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 APD50 in MNCs. In summary, our findings demonstrate 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.