High Calcium Permeability of Serotonin 5‐HT₃ Receptors on Presynaptic Nerve Terminals from Rat Striatum

Abstract

Abstract:The serotonin 5-HT3 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-HT3 receptors induce Ca 2~influx. Whereas postsynaptic 5-HT 3 receptors induce depolarization, being permeant to Naãnd K~, the basis of presynaptic 5-HT3 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-HT3 receptor agonist, induced increases in internal free Ca 2~concentration ([Ca2~]) and exocytosis in a subset of corpus striatal synaptosomes. mCPBG-induced increases in [Ca2~]ranged from 1.3 to 1 .6 times over basal values and were inhibited by 10 nM 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-o-glucamine), to prior depolarization induced on addition of 20 mM K~, or to voltage-gated Ca 2~channel blockade by 10 p~M Co2~/Cd2õrbyl ,uMw-conotoxin MVIIC/1~tMw-conotoxin GVIA/200 nM agatoxin TK. In contrast, the Ca2ĩ nflux induced by 5-HT 3 receptor activation in NG1 08-15 cells by 1 ,tiM mCPBG was substantially reduced by 10.tMCo 2~/Cd2ãnd was completely blocked by 1 ,uM nitrendipine, an L-type Ca2~channel blocker. We conclude that in contrast to the perikaryal 5-HT 3 receptors, presynaptic 5-HT3 receptors appear to be uniquely calcium-permeant. Key Words: Serotonin 5-HT3 receptorPresynaptic regulation-Synaptosomes-Confocal microscopy-Internal free Ca 2~concentration measurements-NG1O8-15 cells.

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

“…It is worth noting that the expression of 5-HT3 receptors in the striatum is low in comparison with the PFC and NA. It has been shown that 5-HT3 receptors are present on striatal, potentially dopaminergic, nerve terminals (Nayak et al, 2000) and that striatal presynaptic 5-HT3 receptors are highly permeable to calcium and may facilitate neurotransmitter release by increasing calcium concentrations within the terminal (Ronde and Nichols, 1998). In the PFC, one study has shown colocalization of 5-HT3 receptors with GABAergic cells (Morales et al, 1996).…”

Endogenous Serotonin Excites Striatal Cholinergic Interneurons via the Activation of 5-HT 2C, 5-HT6, and 5-HT7 Serotonin Receptors: Implications for Extrapyramidal Side Effects of Serotonin Reuptake Inhibitors

“…Among 5-HT receptors, only 5-HT3 is a ligand-gated ion channel, whereas the other receptors belong to the G-proteincoupled receptor (GPCR) superfamily. The striatum expresses a variety of 5-HT receptors: 5-HT1B and 5-HT1E (Bruinvels et al, 1994), 5-HT2A and 5-HT2C (Ward and Dorsa, 1996), 5-HT3 (Blandina et al, 1989;Rondé and Nichols, 1998), 5-HT4 (Jakeman et al, 1994;Waeber et al, 1994;Gerald et al, 1995;Patel et al, 1995), and 5-HT6 (Ruat et al, 1993;Ward and Dorsa, 1996;Gerard et al, 1997). The striatal expression of 5-HT7 is controversial (Vizuete et al, 1997;Martin-Cora and Pazos, 2004).…”

Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner

“…3 Postsynaptic 5-HT 3 receptors are present on g-aminobutyric acid (GABA) ergic interneurons, mediating fast synaptic neurotransmission in the CNS, 4,5 while presynaptic 5-HT 3 receptors modulate the release of several neurotransmitters in various brain regions. 2,6-10 Since 5-HT 3 receptors are highly expressed in the caudate nucleus, putamen, hippocampal and amygdala regions, 1,7 it has been suggested that selective 5-HT 3 receptor antagonists may have psychotropic effects.…”

“…21 With the exception of clozapine, 22,23 an interaction of neuroleptics with the 5-HT 3 receptor has not been described so far. If neuroleptics are functional antagonists at 5-HT 3 receptors, this might contribute to the pharmacological profile of these antipsychotic agents. Therefore, we studied whether neuroleptics exert antagonistic effects at endogenous neuronal 5-HT 3 receptors and at human 5-HT 3A receptors stably expressed in human embryonic kidney (HEK) cells.…”