N-terminal galanin-(1-16) fragment is an agonist at the hippocampal galanin receptor.

Abstract

The galanin N-terminal fragment [galanin-(1-16) The 29-amino-acid-long C-terminal amidated peptide galanin (GAL) (1) has been shown to be widely distributed in the central nervous system of mammals (2-6). GAL-like immunoreactivity has been localized, among other brain regions, in the septal area (4-8) where GAL coexists with acetylcholine in rat (7) and monkey (9) in a subpopulation of cholinergic cell bodies projecting to the hippocampus. and equilibrium binding studies with 1251I-labeled GAL (125I-GAL) have shown a high density of putative high-affinity GAL receptors in the ventral part of the hippocampus (13).In the ventral, but not in the dorsal, hippocampus GAL has been shown to inhibit, in a dose-dependent manner, the release of acetylcholine both in vitro and in vivo (12). A possible role for GAL as presynaptic modulator of the cholinergic function in the ventral hippocampus has been suggested by a recent electrophysiological study (14) and a behavioral study (15). Interactions between acetylcholine and GAL in the ventral hippocampus are not restricted to presynaptic sites but also involve actions that are considered postsynaptic (16) such as the GAL-mediated inhibition of the muscarinic agonist-stimulated breakdown of inositol phospholipids in the ventral hippocampus (17) and GAL inhibition of acetylcholine on a t-maze memory task in ventral forebrain lesioned rats (33).Previous studies carried out on intestinal smooth muscle showed the importance of the N-terminal portion of GAL for biological activity (18,19). Furthermore, N-terminal GAL fragments and analogs were able to mimic the effects of GAL on the pancreatic 83-cell line Rin m 5F, inhibiting forskolinstimulated cAMP production and insulin release (20).In this study, we focus our attention on the structureactivity relationship for the N terminus of GAL at receptors in the ventral hippocampus of the rat. Using equilibrium binding and autoradiographic techniques, we compare the synthetic N-terminal fragment GAL-(1-16) with rat GAL-(1-29) for its ability to displace 1251I-GAL from its receptors.GAL-(1-16) is also tested for its ability to inhibit the scopolamine-induced acetylcholine release in vivo and carbacholstimulated inositol phospholipid breakdown in a slice preparation from the rat ventral hippocampus. The importance of [Trp2] in the activity of the N-terminal fragment is examined.

Galanin Inhibits Continuous and Phasic Firing in Rat Hypothalamic Magnocellular Neurosecretory Cells

“…Indeed, the reversal potential of hyperpolarizing responses recorded in ACSF (approximately Ϫ70 mV) did not correspond exactly to values previously determined to characterize K ϩ currents recorded under similar conditions (e.g., Ϫ97 mV) (Bourque, 1988). Moreover, the shift in reversal potential observed on re- Although only one GAL receptor is currently defined by molecular cloning (Habert-Ortoli et al, 1994;Gustafson et al, 1996), various subtypes of GAL receptors are thought to exist in the brain (Fisone et al, 1989;Hedlund et al, 1992Hedlund et al, , 1994Wynick et al, 1993). colleagues (1992, 1994) have characterized a receptor in the brain that has a high affinity for GAL [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] but will not bind GAL .…”

“…In our studies both GAL 1-29 and GAL 1-16 were found to be equipotent in their effects (IC 50 , ϳ10 nM), suggesting that neither of these receptor subtypes is involved in mediating the inhibitory actions of GAL on MNCs. The receptor activated here, however, seems to be similar to that described in the ventral hippocampus (Fisone et al, 1989), which recognizes both GAL 1-29 and the N-terminal fragment GAL [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] .…”

Characterization of a high-affinity galanin receptor in the rat anterior pituitary: absence of biological effect and reduced membrane binding of the antagonist M15 differentiate it from the brain/gut receptor.

“…The many published structure-activity studies on the effects of galanin fragments and analogues on the GAL-R1 (25)(26)(27)(28)(29)(30)(31) have demonstrated that the active receptor binding part of the peptide resides at the N-terminal portion of the peptide. The presence ofthe unmodified, first two N-terminal amino acid residues is particularly important for retention of high biological potency, since galanin 2-29 and 1-15 are nearly as potent biologically and at receptor displacement as the full 1-29, whereas 3-29, 10-29, and 20-29 are inactive.…”

Cloning and Expressional Characterization of a Novel Galanin Receptor

“…Pharmacological studies with several peptidic agonists and antagonists of galanin receptor suggest the existence of multiple receptor subtypes (7)(8)(9). The first of these receptors (GalR1) has been cloned from several species (10 -13).…”