Prejunctional Effects of Neuropeptide Y and Its Role as a Cotransmitter

Abstract

Neuropeptide Y (NPY) has been shown to be colocalized and coreleased with noradrenaline (NA) and adenosines-5′-triphosphate (ATP) in most sympathetic nerves in the peripheral nervous system, especially those innervating blood vessels. There is also convincing evidence that NPY exerts prejunctional modulatory effects on transmitter release and synthesis. Moreover, there are numerous examples of postjunctional interactions that are consistent with a cotransmitter role for NPY at various sympathetic neuroeffector junctions. This chapter will provide convincing evidence that NPY does function physiologically as the third sympathetic cotransmitter together with NA and ATP. The functions of NPY include: (a) direct postjunctional contractile effects; (b) potentiation of the contractile effects of the other sympathetic cotransmitters, NA and ATP; and (c) inhibitory modulation of the nerve stimulation-induced release of all three sympathetic cotransmitters. Studies with selective NPY- Y1 antagonists provide evidence that the principal postjunctional receptor is of the Y1 subtype although information is incomplete and other receptors are also present at some sites and may exert physiological actions. Studies with selective NPY- Y2 antagonist suggest that the principle prejunctional receptor is of the Y2 subtype both in the periphery and central nervous system (CNS). Again, there is evidence for a role for other NPY receptors and clarification awaits the further development of selective antagonists. NPY can also act prejunctionally to inhibit the release of acetylcholine, calcitonin gene related peptide (CGRP) and substance P. In the CNS, NPY exists as a cotransmitter with catecholamines in some neurons and with peptides and mediators in other neurons. A prominent action of NPY is the presynaptic inhibition of the release of various neurotransmitters including NA, dopamine (DA), gamma-aminobutyric acid, glutamate, serotonin as well as inhibition or stimulation of various neurohormones such as luteinizing hormone (LH), luteinizing hormone releasing hormone, vasopressin, oxytocin as well as others. Evidence also exists for stimulation of NA and DA release. NPY also acts on autoreceptors to inhibit the release of itself. There is evidence that NPY may use several mechanisms to produce its prejunctional/presynaptic effects including: inhibition of calcium channels, activation of potassium channels and perhaps regulation of the vesicle release complex at some point post calcium entry. NPY may also play a role in several pathophysiological conditions. The therapeutic manipulation of NPY release and the development of further selective agonists and antagonist should to be an important goal of future research in order to further understand the physiological and pathophysiological role of NPY.