Neuropeptides and their receptors: innovative science providing novel therapeutic targets

Abstract

This review examines our current understanding of the roles of some of the best known neuropeptides that have played major roles in our combined research programmes. Evidence obtained from over 75 years of research shows involvement of these transmitters in a wide range of organs relevant to cardiovascular, respiratory, cutaneous, neuronal and intestinal systems. There is an increasing understanding of the mechanisms involved in the release of the peptides (substance P and calcitonin gene-related peptide (CGRP)) from sensory nerves or, neuropeptide Y (NPY) from sympathetic, parasympathetic and nonadrenergic, noncholinergic (NANC) neurons. Responses in target tissues result from interactions of the neuropeptides, or related forms, with specific G-protein coupled receptors (GPCRs or 7 transmembrane-spanning, 7TM proteins) that belong to either rhodopsin-like, class 1 (neurokinin (NK) and NPY Y receptors) or secretin-like, class 2 GPCRs (CGRP receptors). The majority of receptors activated by our chosen neuropeptides are now cloned, with knowledge of preferred agonists and selective antagonists for many receptor subtypes within these families. The study of neuropeptides in animal models has additionally revealed physiological and pathophysiological roles that in turn have led to the ongoing development of new drugs, through utilization predominantly of antagonist activities.

Figure 1

Effect of SP and CGRP on erythema in Caucasian human skin. The pictures were taken 10 min after injection of either increasing doses of SP (upper trace) or increasing doses of CGRP (lower trace) in the volar aspect of the same human forearm. The highest dose of SP (10 pmol) induced a typical triple response consisting of oedema formation (wheal) at the injection site, local reddening and a flare, due to a sensory nerve-mediated axon reflex that spread around the flare. Mast cell-derived histamine plays a major role in this response as it is blocked by histamine H₁ antagonists. Lower doses of SP induced a minimal response. By comparison, all doses of CGRP induced erythema. While the response to SP was transient, that to CGRP was long lasting (not shown).

Figure 2

Schematic diagram depicting events following injury to skin. Injury (1) is often followed by activation of mast cells and release of histamine. Histamine then activates sensory neurones via H₁ receptors (2) to stimulate orthodromic stimulation to spinal cord and antidromic stimulation to surrounding skin that leads to neuropeptide release. Substance P can act via NK₁ receptors on endothelial cells of postcapillary venules or possibly by stimulating further histamine release from mast cells, to mediate plasma extravasation at the site of trauma (3). Substance P can also increase blood flow; however, it is CGRP, acting via CGRP receptors that is best known as a potent and long lasting microvascular dilator (4) and probably the mediator of the flare that surrounds the site of injury.

Figure 3

The multiple actions of NPY, together with circulating PYY, PYY(3–36) upon perivascular sympathetic nerve terminals. There are three mechanisms of interaction between NPY and noradrenaline (NA) at this neuroeffector junction: (a) NPY and NA act independently and postjunctionally at different receptors to initiate vasoconstriction; (b) NPY enhances the post-junctional effect of NA and in (c) NPY suppresses the release of NA (and NPY also, not shown). Taken from Edvinsson et al. (1987).

Figure 4

Schematic diagram depicting the sites of action of NPY from enteric neurons and endocrine PYY upon different targets in normal mouse colon mucosa. Direct activation of epithelial Y₁ receptors by NPY and PYY will inhibit epithelial anion (Cl⁻) secretion. Veratridine nonselectively stimulates all intrinsic submucosal neurons. NPY released from submucosal secretomotor neurons can autoinhibit NPY release (a Y₂ receptor-mediated effect) and also, when released from interneurons can inhibit (again via Y₂ receptors) other NANC secretomotor (e.g. VIP-ergic) neurons. Endocrine PYY may coactivate neuronal Y₂ receptors as well as the epithelial Y₁ receptors (predominant in mouse and human colon). Both mechanisms result in a sustained inhibition of epithelial Cl⁻ secretion. The NANC neurotransmitter in the final secretomotor neuron has not yet been positively identified, but it is most likely to be VIP that causes the cAMP-dependent epithelial Cl⁻ secretion.