Substance P
Substance P is a polypeptide containing 11 amino acid residues that is found in the intestine, various peripheral nerves, and many parts of the CNS. It is one of a family of polypep tides called tachykinins that differ at the amino terminal end but have in common the carboxyl terminal sequence of Phe-X Gly-LeuMet-NH2 , where X is Val, His, Lys, or Phe. Other members of the family include neurokinin A and neurokinin B.
There are three neurokinin receptors (NK1–NK3 ), which are metabotropic GPCR. Substance P is the preferred ligand for NK1 receptors in the CNS, and activation of this receptor leads to increased formation of IP3 and DAG.
Substance P is found in high concentrations in the endings of primary afferent neurons in the spinal cord, and it is probably the mediator at the first synapse in the pathways for pain transmission in the dorsal horn. It is also found in high concentrations in the nigrostriatal system, where its concentration is proportional to that of dopamine, and in the hypothalamus, where it may play a role in neuroendocrine regulation. Upon injection into the skin, it causes redness and swelling, and it is probably the mediator released by nerve fibers that is responsible for the axon reflex. In the intestine, it is involved in peristalsis. Several recently developed centrally active NK-1 receptor antagonists have been shown to have antidepressant activity. They have also been used as antiemetics in patients undergoing chemotherapy.
Opioid Peptides
The brain and the gastrointestinal tract contain receptors that bind morphine. The search for endogenous ligands for these receptors led to the discovery of two closely related pentapeptides (enkephalins) that bind to these opioid receptors: met enkephalin and leu-enkephalin. These and other peptides that bind to opioid receptors are called opioid peptides. The enkephalins are found in nerve endings in the gastrointestinal tract and many different parts of the brain, and they appear to function as synaptic transmitters. They are found in the substantia gelatinosa and have analgesic activity when injected into the brainstem. They also decrease intestinal motility. Enkephalins are metabolized primarily by two peptidases: enkephali nase A, which splits the Gly-Phe bond, and enkephalinase B, which splits the Gly-Gly bond. Aminopeptidase, which splits the Tyr-Gly bond, also contributes to their metabolism.
Like other small peptides, the endogenous opioid pep tides are synthesized as part of larger precursor molecules. More than 20 active opioid peptides have been identified. Unlike other peptides, however, the opioid peptides have a number of different precursors. Each has a prepro form and a pro form from which the signal peptide has been cleaved. Proenkephalin was first identified in the adrenal medulla, but it is also the precursor for met-enkephalin and leu-enkephalin in the brain. Each proenkephalin molecule contains four met-enkephalins, one leuenkephalin, one octapeptide, and one heptapeptide. Proopiomelanocortin, a large precursor molecule found in the anterior and intermediate lobes of the pituitary gland and the brain, contains β-endorphin, a poly peptide of 31 amino acid residues that has metenkephalin at its amino terminal. There are separate enkephalin-secreting and β-endorphin–secreting systems of neurons in the brain. β-Endorphin is also secreted into the bloodstream by the pituitary gland. A third precursor molecule is prodynorphin, a protein that contains three leuenkephalin residues associated with dynorphin and neoendorphin. Different types of dynorphins are found in the duodenum and the posterior pituitary and hypothalamus; β-neoendorphins are also found in the hypothalamus.
There are three classes of opioid receptors: μ, κ, and δ with various subtypes of each of these, but genes encoding only one subtype for each has been identified and characterized. As shown in Table 1, they differ in physiologic effects and affinity for various opioid peptides. All three are GPCR, and all inhibit adenylyl cyclase. Activation of μ receptors increases K+ conductance, hyperpolarizing central neurons and primary afferents. Activation of κ receptors and δ receptors closes Ca2+ channels.
Table1. Physiologic effects produced by stimulation of opioid receptors.
Other Polypeptides
Numerous other polypeptides are found in the brain. For example, somatostatin is found in various parts of the brain, where it may function as a neurotransmitter with effects on sensory input, locomotor activity, and cognitive function. In the hypothalamus, this growth hormone—inhibiting hormone is secreted into the portal hypophysial vessels; in the endocrine pancreas, it inhibits insulin secretion and the secretion of other pancreatic hormones; and in the gastrointestinal tract, it is an important inhibitory gastrointestinal regulator. A family of five different somatostatin receptors have been identified (SSTR1 through SSTR5). All are GPCR that inhibit adenylyl cyclase and exert various other effects on intracellular messenger systems. It appears that SSTR2 mediates cognitive effects and inhibition of growth hormone secretion, whereas SSTR5 mediates the inhibition of insulin secretion.
Vasopressin and oxytocin are not only secreted as hormones but also are present in neurons that project to the brainstem and spinal cord. The brain contains bradykinin, angiotensin II, and endothelin. The gastrointestinal hormones, including vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK-4 and CCK-8), are also found in the brain. There are two kinds of CCK receptors in the brain, CCK-A and CCK-B. CCK-8 acts at both binding sites, whereas CCK-4 acts at the CCK-B sites. Gastrin, neurotensin, galanin, and gastrin-releasing peptide are also found in the gastrointestinal tract and brain. Neurotensin, VIP, and CCK receptors have been cloned and shown to be GPCR. The hypothalamus contains both gastrin 17 and gastrin 34. VIP produces vasodilation and is found in vasomotor nerve fibers. The functions of these peptides in the nervous system are unknown, although some of the peptides also expressed in the gastrointestinal system have been implicated in satiety.
Calcitonin gene-related peptide (CGRP) is present in the CNS and peripheral nervous system, gastrointestinal tract, cardiovascular system, and urogenital system. CGRP is co-localized with either substance P or acetylcholine. CGRP like immunoreactivity is present in the circulation, and injection of CGRP causes vasodilation. CGRP and the calcium-lowering hormone calcitonin are both products of the calcitonin gene. In the thyroid gland, splicing produces the mRNA that codes for calcitonin, whereas in the brain, alternative splicing pro duces the mRNA that codes for CGRP. CGRP has little effect on Ca2+ metabolism, and calcitonin is only a weak vasodilator. Release of CGRP from trigeminal afferent fibers may contribute to the pathophysiology of migraine. Actions of this peptide are mediated by two types of metabotropic CGRP receptors.
Neuropeptide Y is a polypeptide that is very abundant throughout the brain and the autonomic nervous system. Neuropeptide Y acts on eight identified receptors: Y1–Y8 ; except for Y3 , these are GPCR. Activation of these receptors mobilizes Ca2+ and inhibits adenylyl cyclase. It acts within the CNS to increase food intake, and Y1 and Y5 receptor antagonists may be used to treat obesity. It also acts in the periphery to cause vasoconstriction. It acts on heteroreceptors on post ganglionic sympathetic nerve terminals to reduce release of norepinephrine.
