Electrophysiological effects of C-type natriuretic peptide in the heart and in the central nervous system: the role of the NPR-C receptor

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C-type natriuretic peptide (CNP) is one member of a group of related peptide hormones, which also includes atrial and brain natriuretic peptides, that elicit a wide range of effects in vertebrates, including humans. The natriuretic peptide C receptor (NPR-C) is functionally linked to an inhibitory G protein (Gi) that inhibits adenylyl cyclase (via the a subunit) and activates phospholipase C (PLC; via the ~y subunit). This thesis describes novel electrophysiological effects of CNP in cardiac myocytes, fibroblasts , and hypothalamic neurons that are specifically mediated by NPR-C. In isolated bullfrog atrial myocytes CNP (1 o-8 M) significantly shortened the duration and decreased the amplitude of the action potential. CNP and the NPR-C selective agonist, cANF (10-8 M), significantly decreased the L-type Ca2 + current Clca(L)) without altering the inward rectifier K+ current indicating that CNP inhibits Ica(L) when it binds NPR-C. To explore the selectivity of CNP effects voltage clamp studies on isolated sinoatrial (SA) node myocytes were performed. In these myocytes CNP and cANF strongly inhibited isoproterenol-stimulated Ica(L) without altering another cAMP sensitive current, Ir. Measurement of EC Gs in Langendorff-perfused mouse hearts revealed the ability of CNP and cANF to decrease heart rate. A similar pattern of results was observed in magnocellular neurosecretory cells (MN Cs) of the hypothalamus. In these neurons, which are responsible for the release of vasopressin and oxytocin, CNP and cANF selectively inhibited Ica(L)· Another voltage gated Ca2+ current, Ica(T), was not modulated by CNP. The inhibition oflca(L) resulted in a decrease in MNC excitability and a shortening of action potential duration in these neurons. In isolated cardiac fibroblasts, CNP and cANF activated an outwardly rectifying current with an apparent reversal potential near O m V. This current was inhibited by the transient receptor potential (TRP) channel blockers Gd3 \ SKF 96365 and 2-APB. The response was also antagonized by the PLC antagonist U73122. Together, these results indicate that CNP activates a TRP channel in cardiac fibroblasts following the activation of PLC by the NPR-C receptor. These data provide the first description of electrophysiological effects of CNP that are mediated by NPR-C in the heart and the hypothalamus.
Bibliography: p. 171-206