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C-type Natriuretic Peptide Inhibits L-type Ca²⁺ Current in Rat Magnocellular Neurosecretory Cells by Activating the NPR-C Receptor

¹Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada; ²Department of Bioengineering, University of California, San Diego, La Jolla, California; and ³Department of Physiology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada

Submitted 18 January 2005; accepted in final form 14 March 2005

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 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 (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.

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