The neuropeptide galanin coexists with norepinephrine and serotonin in neural systems mediating emotion. Previous findings suggested that galanin modulates anxiety-related behaviors in rodents. Three galanin receptor subtypes have been cloned; however, understanding their functions has been limited by the lack of galanin receptor subtype-selective ligands. To study the role of the galanin GAL-R1 receptor subtype in mediating anxiety-related behavior, we generated mice with a null mutation in the Galr1 gene. GAL-R1 À/À are viable and show no abnormalities in health, neurological reflexes, motoric functions, or sensory abilities. On a battery of tests for anxietylike behavior, GAL-R1 À/À showed increased anxiety-like behavior on the elevated plus-maze test. Anxiety-related behaviors on the light/dark exploration, emergence, and open field tests were normal in GAL-R1 À/À. This test-specific anxiety-like phenotype was confirmed in a second, independent cohort of GAL-R1 null mutant mice and +/+ controls. Principal components factor analysis of behavioral scores from 279 mice suggested that anxiety-like behavior on the elevated plus-maze was qualitatively distinct from behavior on other tests in the battery. In addition, exposure to the elevated plus-maze produced a significantly greater neuroendocrine response than exposure to the light/dark exploration test, as analyzed in normal C57BL/6J mice. These behavioral findings in the first galanin receptor null mutant mouse are consistent with the hypothesis that galanin exerts anxiolytic actions via the GAL-R1 receptor under conditions of relatively high stress.
Expression of the neuropeptide galanin is markedly upregulated within the adult dorsal root ganglion (DRG) after peripheral nerve injury. We demonstrated previously that the rate of peripheral nerve regeneration is reduced in galanin knock-out mice, with similar deficits observed in neurite outgrowth from cultured mutant DRG neurons. Here, we show that the addition of galanin peptide significantly enhanced neurite outgrowth from wild-type sensory neurons and fully rescued the observed deficits in mutant cultures. Furthermore, neurite outgrowth in wild-type cultures was reduced to levels observed in the mutants by the addition of the galanin antagonist M35 [galanin(1-13)bradykinin(2-9)]. Study of the first galanin receptor (GalR1) knock-out animals demonstrated no differences in neurite outgrowth compared with wild-type animals. Similarly, use of a GalR1-specific antagonist had no effect on neuritogenesis. In contrast, use of a GalR2-specific agonist had equipotent effects on neuritogenesis to galanin peptide, and inhibition of PKC reduced neurite outgrowth from wild-type sensory neurons to that observed in galanin knock-out cultures. These results demonstrate that adult sensory neurons are dependent, in part, on galanin for neurite extension and that this crucial physiological process is mediated by activation of the GalR2 receptor in a PKC-dependent manner.
Expression of muscarinic receptors in rat islets, RINm5F cells, and INS-1 cells was established by reverse transcriptase-polymerase chain reaction (RT-PCR) a n d q u a n t i fied by RNase protection. Both methods indicated that m3 and m1 receptors were expressed approximately equally in the various cellular preparations and to a much greater extent than the m5 subtype. However, the cell lines, especially RINm5F cells, expressed less of a given receptor subtype than did islets. Immunohistochemistry indicated that m3 receptors were expressed throughout the islet core. Binding studies using the R elease of acetylcholine from vagal efferents on pancreatic islet cells plays an important role in the cephalic phase of insulin secretion. Thus, the neurotransmitter directly evokes a rise in plasma insulin in the immediate postprandial period in rats and humans, before any glycemic elevation (1,2). Acetylcholine also potentiates nutrient-stimulated insulin secretion, an effect best demonstrated in vitro, where confounding postabsorptive influences occurring in vivo are absent (1,2). Thus, potentiation has been demonstrated using perfused pancreas (3) and isolated islets (4-6), and the direct stimulation has been shown in pancreas perfusions (3), insulinsecreting cell lines (7), and cultured (6,8) but not freshly isolated (9,10) islets. The latter preparation might be less responsive because of damage to acetylcholine receptors on the cell surface sustained during collagenase digestion, which is necessary for islet isolation. Acetylcholine has also been shown to prime the -cell in vitro such that a subsequent glucose challenge elicits a larger secretory response than in an unprimed cell (5).The effects of acetylcholine on the -cell are mediated by muscarinic cholinergic, rather than nicotinic, receptors (1,2,5,10). Five subtypes of muscarinic receptors have been d e fined at the molecular level (m1-m5), all of which are members of the G-protein coupled receptor family (11). The m2 and m4 receptor subtypes couple mainly via pertussis toxin-sensitive G-proteins to inhibition of adenylate cyclase. The functional responses of the m1, m3, and m5 subtypes are generally insensitive to pertussis toxin, are mediated via Gq/11, and are associated with activation of phospholipase C (PLC) and hydrolysis of phosphatidylinositol 4,5-bisphosphate (Ptd InsP2) (11). The signaling pathways activated by muscarinic receptor agonists in -cells are insensitive to pertussis toxin (12,13) and are not accompanied by inhibition of adenylate cyclase (6,9), but they do involve Ptd InsP2 hydrolysis (7,8,10,13). Thus, functional islet muscarinic receptors fall into the m1/m3/m5 category, rather than m2/m4. This is broadly consistent with some limited pharmacological analyses suggesting that m3 is the major receptor subtype present in pancreatic -cells (14-17). However, mRNA for other receptor subtypes has also been detected by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of extracts of rat islets (17) and insulin-secreting RINm5F c...
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