Neuropeptide y modulates L-type Ca2+ current during heart development.

An interesting and potentially very important study 1 in this issue of Circulation Research reports that during development of the mammalian heart, neuropeptide Y can significantly increase L-type Ca current, thereby enhancing heart rate and strength of contraction. In this study, a combination of targeted deletion of the NPY gene, electrophysiological recordings, and immunoblot analysis of Ca channel 1C expression is used in an experimental design that involves study of hearts from preand postnatal animals at predetermined stages.1 These findings can perhaps be put in context by the following brief review of NPY physiology and pharmacology in mammalian tissue. Neuropeptide Y (NPY) was identified by Tatemoto and Mutt in 1982 through use of a novel chemical assay that detected the amidated C-terminal tyrosine residue of this 36-amino acid peptide.2,3 Isolated first from brain, it was soon discovered to be widely distributed throughout the body, primarily in postganglionic sympathetic nerves and often colocalized with norepinephrine.4 Indeed, NPY is the most widely distributed and abundant neuropeptide in the nervous system. NPY shares structural and functional homology with two other 36-amino acid peptides, pancreatic polypeptide (PP) and peptide YY (PYY).4 All three have a characteristic U-shaped tertiary structure termed the PP-fold.5 Four G protein–coupled receptors for the PP-fold peptides have been cloned; these are termed the Y1, Y2, Y4, and Y5 receptors. The Y3 receptor has not been cloned, although a y6 receptor has been identified by molecular methods. It is designated with a lowercase “y” as, at present, it appears not to be functional.5 PP and PYY are primarily localized in endocrine and enteroendocrine cells of the pancreas and gastrointestinal tract, respectively.4 The well-established physiological actions of NPY and the other members of this family are extensive and include stimulation of food intake,6 inhibition of anxiety,7 and control of seizures8 in the CNS, presynaptic inhibition of neurotransmitter release in the CNS and periphery,4,8 and vasoconstriction,9,10 inhibition of insulin release,6 regulation of gastrointestinal secretion,11 and other actions in the periphery. In most cells studied, the effects of NPY are mediated by the four receptors mentioned above linked to pertussis toxin–sensitive G proteins of the Gi and Go family.5 While inhibition of adenyl cyclase is a feature of the heterologous expression of the cloned receptors in cell systems, it does not fully explain the range of responses seen after stimulation of NPY receptors in tissues.4,5 It has been suggested that a pertussis toxin–insensitive Gq protein may also mediate the effects of Y-receptor stimulation. An interesting feature of NPY signaling is that NPY in its native form is a potent ligand for the Y1 receptor. A tissue-bound peptidase, dipeptidyl peptidase IV (CD26), cleaves the N-terminus to produce NPY3-36, which is a potent endogenous ligand for the Y2 and Y5 receptors.12 NPY is found in the heart in neurons of the intracardiac ganglia and in postganglionic sympathetic nerves that innervate cardiac blood vessels, the intracardiac ganglia, endocardium, and myocardium.13–15 Fibers containing NPY innervate intrinsic parasympathetic cardiac neurons. During development in the rat, there is a gradual increase in the density of the NPY-containing neural elements. This is first detected during gestation, increases through to the first 3 weeks of postnatal life, and then remains stable through adulthood.16 NPY is contained in large dense-cored secretory vesicles and appears to be stored separately from norepinephrine.17 It appears that the release of NPY is frequency-dependent, with greater release at higher frequencies of stimulation. NPY released from sympathetic nerve terminals can have direct postjunctional effects on cardiovascular tissues or can serve as a presynaptic regulator of neurotransmitter release.9,10,18–20 Y1 and Y2 receptors appear to mediate most of the cardiovascular effects of NPY, although the Y3 receptor has been implicated in the actions of NPY in the heart.4,21,24 Presynaptic inhibition of neurotransmitter release, postsynaptic enhancement of Ito and reduction of If in cardiomyocytes,23 and the developmental regulation of cardiac ion channels (which appears to require synergistic interactions with norepinephrine) are due to Y2-receptor activation.18–21 The postsynaptic vasoconstrictor effect of NPY on coronary blood vessels relies predominantly on Y1-receptor activation.9 In addition to this well-defined neurotransmitter role, NPY can stimulate or modulate angiogenesis.18,25,26,29 Increased plasma levels of NPY correlate with severity of left ventricular hypertrophy in vivo, and NPY levels are known to increase in congestive heart failure in rats and humans, whereas overall plasma peptide content decreases.27,30 It is likely that this increase in NPY concentration reflects an increased density of sympathetic nerve terminals, although it should be noted that NPY is also found in platelets, immune cells, and endothelial cells.4,30 NPY acts at Y2 and Y5 The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Physiology and Biophysics (A.E.G.L., K.A.S., W.R.G.), University of Calgary, Calgary, Alberta, Canada; Department of Bioengineering (W.R.G.), Whitaker Institute of Biomedical Engineering University of California San Diego, Calif. Correspondence to Dr Wayne R. Giles, Department of Bioengineering, Whitaker Institute of Biomedical Engineering, PFBG 384, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0412. E-mail [email protected] (Circ Res. 2003;93:891-892.) © 2003 American Heart Association, Inc.