Ezhuthachan College of Pharmaceutical Sciences, Marayamuttom, Neyyattinkara, Thiruvananthapuram, Kerala

*Corresponding Author E-mail: merlinbinu76@yahoo.co.in

ABSTRACT:

Neuropeptides are peptidergic neurotransmitters, which are produced by neurons. Most neuropeptides where initially discovered in the brain, but later it became clear that a large number of these peptides is also present in secretory vesicles of unmylinated sensory nerve endings of the enteric nervous system. Neuropeptides in enteric nervous system include calcitonin gene-related peptide, vasoactive intestinal polypeptide, somatostatin and substance P, gatrin releasing peptide, neurotensin, motiline and galanin. Many of these peptides are also found in enterocytes in the mucosa. These neuropeptides are released from the enterocytes as a paracrine or endocrine substance under the influence enteric nervous system.

KEY WORDS:

INTRODUCTION:

Neuropeptides are small protein-like molecules (peptides) used by neurons to communicate with each other. They are neuronal signaling molecules that influence the activity of the brain in specific ways. Different neuropeptides are involved in a wide range of brain functions, including analgesia, food intake, metabolism, reproduction, social behaviours, learning and memory. Neuropeptides are related to peptide hormones and in some cases peptides that function in the periphery as hormones also have neuronal functions as neuropeptides. Neuropeptides are secreted from neuronal cells (primarily neurons but also glia for some peptides) and signal to neighboring cells (primary neurons). In contrast, peptide hormones are secreted from neuroendocrine cells and travel through the body to distant tissues where they evoke a response.

Fig.1 The structure of a neuropeptide

Biogenesis of neuropeptides:

The synthesis of neuropeptide is like the synthesis of any secretory protein made by the cell. First, within the cell nucleus, gene transcription takes place, during which a specific peptide-coding sequence of DNA is used as a template to construct a corresponding strand of messenger RNA. The mRNA then travels to a ribosome, where the process of translation begins. During translation, the sequence of nucleotides that make up the mRNA act as a code to string together a corresponding sequence of amino acids that will eventually become the neuropeptide needed at the terminal. Before this molecule can be transported to the terminal for release into the synaptic cleft, it must be processed in the endoplasmic reticulum (ER), packaged in the golgi apparatus, and transported in storage vesicles down the axon to the terminal.

The endogenous opioids, a large family of neuropeptides that act as natural analgesics, provide a good example of how post-translational processing of just one precursor molecule can result in a whole spectrum of different, but related, neurotransmitters. Selective cleaving and splicing of each just three precursor molecules results in the production of the various opioids included in this family of neurotransmitters.

Once they are synthesized, neurotransmitters, both small molecules and neuropeptides, are stored in vesicles within the axon terminal until an action potential arrives and they are released. Most small-molecule neurotransmitters are stored in small vesicles that range from 40 to 60 nm in diameter and, in electron micrographs, appear to have clear centers. The vesicles that store neuropeptides are larger, ranging from 90 to 250 nm in diameter. These vesicles appear dark and electron-dense in electron micrographs.

Neuropeptide receptors:

G-protein coupled receptors form the most important receptor group in the signalling process of the neuropeptides of the enteric nervous system. The receptors consist of 7 transmembrane alpha-helical structures and intracellular and extracellular domains. The G-protein coupled receptors can be divided into three families, A, B and C. The rhodopsin-like family A is the largest subgroup and the ligand binding site of the A family is primarily located in the transmembrane region. The secretin-like receptor family B can bind several neuropeptides and peptide hormones. For this receptor family the binding sites are located at the relatively long NH₂-terminus, sometimes in combination with the extracellular transmembrane regions. The third group, the metabotropic glutamate receptor-like family C, is the smallest group with only 17 members; they have both a long NH₂-terminus and COOH- terminus, with the binding site in the NH₂-terminus. Intracellularly a G-protein, which consists of an α, β and γ subunit, is connected with the receptor. Binding of an agonist to the receptor’s active site induces a conformational change that converts the receptor to its active state. This leads to the exchange of G-protein-bound GDP for GTP, after which the G-protein is disconnected from the receptor and the α subunit dissociates from the β γ dimer. The α subunit can subsequently activate several second messenger pathways.^[1]

Distribution of neuropeptides:

Neuropeptides are distributed in the central nervous system and peripheral nervous system. The neuropeptides in the central nervous system are neuropeptide Y (NPY), melanocortins, and amphetamine-regulated transcript. Signals from the periphery importantly influence the energy status of the body, as well as the amount of fat and glucose in the blood. These signals are hormones secreted from various organs in connection with meal initiation satiety and long-term energy changes. The most important are peptide YY (PYY), pancreatic polypeptide (PP), cholecystokinin (CCK), oxyntomodulin (OXM), GLP-1, gastric inhibitory polypeptide (GIP), bombesin, leptin, adipo nectin, resistin, visfatin and ghrelin.

Physiological functions of neuropeptides:

Cardiovascular response:

The endogenous Neuropeptide Y acting on the Y1 receptor is likely to account for the long-lasting component of sympathetic vasoconstriction in response to high-frequency stimulation. It was reported that the incubation of the subcutaneous arteries with Y1 receptor antisense oligodeoxynucleotides attenuated NeuropeptideY-induced vasoconstriction. Furthermore, Y1 receptor-deficient mice showed a complete absence of blood pressure responses to NeuropeptideY, suggesting the importance of Y1 receptors in the NeuropepideY-mediated cardiovascular response. However, it was also reported that the depressor effect of intrathecal NeuropeptideY injection was primarily mediated by a Y2 receptor. Furthermore, a Y2 receptor agonist evoked vasoconstriction in the spleen, while a Y2 receptor antagonist BIIE0246 antagonized the response. These suggest that the Y2 receptor is also involved in NPY/PYY-evoked vasoconstriction^[^2] .

Circadian rhythms:

NeuropeptideY has been implicated in the phase shifting of circadian rhythms. Microinjection of a Y2 receptor agonist produced phase advances that were significantly greater than those produced by the injection of a Y1 receptor agonist. This suggests that NeuropeptideY phase shifts circadian rhythms via the Y2 receptor.^[3] There is, however, some evidence that the Y1/Y5 receptors, in addition to the Y2 receptor, may also be involved in the mechanism of NeuropeptideY action by altering the levels of circadian clock-related genes^[^3].

Food intake and energy expenditure:

NeuropeptideY has been implicated to be a central stimulator of feeding behaviour by interacting with a number of other hormones and neuroregulators that play roles in the regulation of body weight. A novel obese gene product, leptin, was found to regulate food intake by inhibiting the synthesis and release of NPY in the central nervous system.It was reported that the mild obesity found in Y1 receptor-deficient mice was caused by impaired insulin secretion and low energy expenditure. Furthermore, NPY-induced food intake was remarkably reduced in Y1-deficient mice. These results suggest the importance of Y1 receptors in the regulation of food intake and body weight through the central control of energy expenditure. It was found that the Y5 receptor was also involved in NPY-induced food intake. The Y5 receptor-deficient mice responded significantly less to NPY-induced food intake than wild-type mice. On the other hand, the results obtained using Y2 receptor-deficient mice indicated an inhibitory role for the Y2 receptor in the central regulation of body weight and food intake. Hypothalamus-specific Y2 receptor-deleted mice showed a significant decrease in body weight and a significant increase in food intake, suggesting an important role of hypothalamic Y2 receptors in body weight regulation. In addition, it was reported that peripheral injection of PYY in rats inhibited food intake and reduced weight gain. PYYalso inhibited food intake in mice, but not in Y2 receptor- deficient mice. This suggests that the anorectic effect requires the Y2 receptor.

Hormone secretion and reproduction:

NeuropeptideY has been known to be a putative neuroregulator of the reproductive axis in the central nervous system. A selective Y5 agonist inhibited LH secretion, while the inhibitory action was fully prevented by Y5 receptor antagonists. It was also shown that Y5 receptor activation suppressed the reproductive axis in both virgin and lactating rats. These results suggest that the actions of Neuropeptide Y on the reproductive axis are predominantly mediated by the Y5 receptor. On the other hand, using Y1 receptor-deficient mice, crucial roles for the Y1 receptor in controlling food intake, the onset of puberty, and the maintenance of reproductive functions were demonstrated.

Anxiety, pain, stress and depression:

It has been shown that NeuropeptideY exhibits anxiolytic, antinociceptive, anti-stress, and anti-depressive actions. Involvement of the Y1 receptor in the anxiolytic-like action of NeuropeptideY was demonstrated. NeuropeptideY may produce not only an anxiolytic effect via the Y1 receptor, but also an anxiogenic effect via the Y2 receptor. It was reported that NeuropeptideY transgenic mice displayed anxiolytic behaviors.^[4]

CONCLUSION:

Major progress has been made in the field of neuropeptides. The peptides have found their receptors, powerful drugs have been developed and novel insights into the regulation of peptide synthesis have been obtained, including the provocative finding of mRNA in axonal processes. Still, the physiological role of neuropeptides is not well defined and transmitter-like functions, modulation and trophic actions have to be considered. With the improved tools now available it should be possible to clarify many of these open questions. The use of peptide agonists and antagonists should help to elucidate the function of neuropeptides in systems of importance for psychopharmacology.

ACKNOWLEDGEMENT:

The authors thank Shri. T.G. Hari Kumar, General Secretary, Ezhuthachan College of Pharmaceutical Sciences, Marayamuttom for providing the necessary facilities.

REFERENCES:

1. Jacoby. E., Bouheal. R., Gerspacher. M., Seuwen. K., The 7 TM G-protein coupled receptor target family. Chem Med Chem. 2006; 1:761-82.

2. Sun X Y, Zaho X H, Erlinge D, et al. (1996) Effects of phosphorothioated neuropeptide Y Y1-receptor antisense oligodeoxynucleotide in conscious rats and in human vessels. Br J Pharmacol 118: 131-136.

3. Huhman K L, Gillespie C F, Marvel C L, Albers H E (1996) Neuropeptide Y phase shifts circardian rhythms in vivo via a Y2 receptor. Neuroreport 7: 1249-1252.

4. Inui A, Okita M, Nakajima M et al. (1998) Anxiety-like behavior in transgenic mice with brain expression of neuropeptide Y. Proc Assoc Am Physicians 110: 171-182.

Received on 19.11.2014 Accepted on 29.11.2014

Asian J. Pharm. Res. 4(4): Oct.-Dec.2014; Page 198-200