GALANIN - 10 YEARS WITH A NEUROENDOCRINE PEPTIDE

Galanin is a 29/30 amino acids long neuropeptide which does not belong to any known peptide family. The N-terminal first 16 amino acids of t he molecule are both necessary and sufficient for receptor recognition and receptor activation, The main pharmacophores of galanin in its ce ntral and pancreatic actions are Gly(1), Trp(2), Asn(5) and Tyr(9), re spectively. The neuropeptide galanin has multiple effects in both the central and peripheral nervous systems. Centrally, galanin potently st imulates fat intake and impairs cognitive performance. Anoxic glutamat e release in the hippocampus is inhibited by galanin and the noradrene rgic tonus in the brain is influenced by a hyperpolarizing action of g alanin in the locus coeruleus. In the spinal cord galanin inhibits spi nal excitability and potentiates the analgesic effect of morphine. In the neuroendocrine system galanin acts in a stimulatory manner on the release of growth hormone and prolactin, and peripherally galanin inhi bits glucose induced insulin release. Galanin also causes contraction of the jejunum. The galanin receptor is a G(i)-protein-coupled, membra ne-bound glycoprotein with an estimated molecular mass of 53 kDa. Seve ral putative tissue specific galanin receptor subtypes have been propo sed on a pharmacological basis. The distribution of galanin receptors and of galanin like immunoreactivity are overlapping in the CNS, both being high in areas such as the locus coeruleus, raphe nucleus and hyp othalamus. Galanin receptor activation leads to a reduced intracellula r Ca2+-concentration, either by direct action on voltage sensitive Ca2 +-channels or indirectly via opening of K+-channels or via inhibition of adenylyl cyclase activity. The lowered intracellular Ca2+ level sub sequently leads to a reduced PLC activity. Galanin also inhibits cGMP synthesis induced by depolarization. A number of synthetic high affini ty galanin receptor antagonists of the peptide type were developed rec ently, which have enabled the elucidation of functional roles of endog enous galanin in several systems. Furthermore, putative subtypes of ga lanin receptors can be distinguished by the use of these new galanin r eceptor ligands.