High Calcium Permeability of Serotonin 5‐HT 3 Receptors on Presynaptic Nerve Terminals from Rat Striatum

The serotonin 5‐HT 3 receptor, a ligand‐gated ion channel, has previously been shown to be present on a subpopulation of brain nerve terminals, where, on activation, the 5‐HT 3 receptors induce Ca 2+ influx. Whereas postsynaptic 5‐HT 3 receptors induce depolarization, being permeant to Na + and K + , the basis of presynaptic 5‐HT 3 receptor‐induced calcium influx is unknown. Because the small size of isolated brain nerve terminals (synaptosomes) precludes electrophysiological measurements, confocal microscopic imaging has been used to detect calcium influx into them. Application of 100 n M 1‐( m ‐chlorophenyl)biguanide (mCPBG), a highly specific 5‐HT 3 receptor agonist, induced increases in internal free Ca 2+ concentration ([Ca 2+ ] i ) and exocytosis in a subset of corpus striatal synaptosomes. mCPBG‐induced increases in [Ca 2+ ] i ranged from 1.3 to 1.6 times over basal values and were inhibited by 10 n M tropisetron, a potent and highly specific 5‐HT 3 receptor antagonist, but were insensitive to the removal of external free Na + (substituted with N ‐methyl‐ d ‐glucamine), to prior depolarization induced on addition of 20 m M K + , or to voltage‐gated Ca 2+ channel blockade by 10 µ M Co 2+ /Cd 2+ or by 1 µ M ω‐conotoxin MVIIC/1 µ M ω‐conotoxin GVIA/200 n M agatoxin TK. In contrast, the Ca 2+ influx induced by 5‐HT 3 receptor activation in NG108‐15 cells by 1 µ M mCPBG was substantially reduced by 10 µ M Co 2+ /Cd 2+ and was completely blocked by 1 µ M nitrendipine, an L‐type Ca 2+ channel blocker. We conclude that in contrast to the perikaryal 5‐HT 3 receptors, presynaptic 5‐HT 3 receptors appear to be uniquely calcium‐permeant.