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(Circulation Research. 2003;93:972.)
© 2003 American Heart Association, Inc.

Integrative Physiology

Neuropeptide Y Is an Essential In Vivo Developmental Regulator of Cardiac I_Ca,L

Lev Protas, Andrea Barbuti, Jihong Qu, Vitalyi O. Rybin, Richard D. Palmiter, Susan F. Steinberg, Richard B. Robinson

From the Department of Pharmacology (L.P., A.B., J.Q., V.O.R., S.F.S., R.B.R.) and Center for Molecular Therapeutics (S.F.S., R.B.R.), Columbia University, New York, NY; and the Department of Biochemistry and Howard Hughes Medical Institute (R.D.P.), University of Washington, Seattle, Wash.

Correspondence to Richard B. Robinson, PhD, Columbia University, Department of Pharmacology, 630 W 168th St, New York, NY 10032. E-mail rbr1{at}columbia.edu

Cell culture studies demonstrate an increase in cardiac L-type Ca²⁺ current (I_Ca,L) density on sympathetic innervation in vitro and suggest the effect depends on neurally released neuropeptide Y (NPY). To determine if a similar mechanism contributes to the postnatal increase in I_Ca,L in vivo, we prepared isolated ventricular myocytes from neonatal and adult mice with targeted deletion of the NPY gene (Npy^-/-) and matched controls (Npy^+/+). Whole-cell voltage clamp demonstrates I_Ca,L density increases postnatally in Npy^+/+ (by 56%), but is unchanged in Npy^-/-. Both I_Ca,L density and action potential duration are significantly greater in adult Npy^+/+ than Npy^-/- myocytes, whereas I_Ca,L density is equivalent in neonatal Npy^+/+ and Npy^-/- myocytes. These data indicate NPY does not influence I_Ca,L prenatally, but the postnatal increase in I_Ca,L density is entirely NPY-dependent. In contrast, there is a similar postnatal negative voltage shift in the I-V relation in Npy^+/+ and Npy^-/-, indicating NPY does not influence the developmental change in I_Ca,L voltage-dependence. Immunoblot analyses and measurements of maximally activated I_Ca,L (in presence of forskolin or BayK 8644) show that the differences in current density between Npy^+/+ and Npy^-/- cannot be attributed to altered Ca²⁺ channel _1C subunit protein expression. Rather, these results suggest that the in vivo NPY-dependent postnatal increase in I_Ca,L density in cardiac myocytes results from regulation I_Ca,L properties by NPY.

Key Words: neuropeptide Y • development • Ca²⁺ channel • innervation • ventricle

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