Distribution of the omega-conotoxin receptor in rat brain. An autoradiographic mapping.
ABSTRACT The distribution of [125I]omega-conotoxin GVIA binding sites, the putative voltage-sensitive calcium channels, was studied by an autoradiographic method in the rat brain. The toxin binding sites were distributed throughout the brain in a highly heterogeneous manner. The highest density of the binding sites was observed in the cerebral cortex, hippocampus, amygdaloid complex, substantia nigra, caudate putamen, superior colliculus, nucleus of the solitary tract, and the dorsal horn of the cervical spine. The glomerular layer of the olfactory bulb, molecular layer of the cerebellar cortex, and posterior lobe of the hypophysis showed intermediate density but the density was higher than in the surrounding areas. The globus pallidus, thalamic areas, inferior olive, and pontine nuclei showed low density, while no binding sites were observed in the white matter tract regions such as the internal and external capsule, corpus callosum, fimbria of the hippocampus, fornix, stria medullaris of the thalamus, and fasciculus retroflexus. This distribution of omega-conotoxin binding sites indicates that the toxin binding sites are localized in those areas of the brain enriched in synaptic connections. This distribution pattern resembles that reported for voltage-sensitive sodium channels but it differs from that of the binding sites of dihydropyridines and verapamil. These results suggest that omega-conotoxin recognizes different molecules from organic calcium channel antagonist binding sites and that omega-conotoxin-sensitive voltage-sensitive calcium channels are concentrated in the synaptic zones and play a key role in the excitation-secretion coupling of neurotransmitters.
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ABSTRACT: The intrinsic electrical properties of neurons are shaped in large part by the action of voltage-gated ion channels. Molecular cloning studies have revealed a large family of ion channel genes, many of which are expressed in mammalian brain. Much recent effort has focused on determining the contribution of the protein products of these genes to neuronal function. This requires knowledge of the abundance and distribution of the constituent subunits of the channels in specific mammalian central neurons. Here we review progress made in recent studies aimed at localizing specific ion channel subunits using in situ hybridization and immunohistochemistry. We then discuss the implications of these results in terms of neuronal physiology and neuronal mechanisms underlying the observed patterns of expression.Annual Review of Physiology 02/2004; 66:477-519. · 19.55 Impact Factor
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ABSTRACT: There are a number of neurologically active ion channel blocking peptides derived from cone snail venom, such as conantokin-G and omega-conotoxin MVIIA. Conantokin-G inhibits NMDA receptors containing the NR2B subunit whereas omega-conotoxin MVIIA blocks N-type Ca(2+) channels. Separately, these peptides induce antinociceptive effects in pre-clinical pain models following intrathecal injection. In the current study, the efficacies of these peptides were determined separately and in combination by intrathecal injection into rats with a spinal nerve ligation, in rats with a spinal cord compression injury and in the formalin test. Separately, both conantokin-G and omega-conotoxin MVIIA dose-dependently attenuated nociceptive responses in all of these models. However, at high antinociceptive doses for both formalin and nerve injury models, omega-conotoxin MVIIA evoked untoward side effects. Using isobolographic analysis, the combination of sub-antinociceptive doses of peptides demonstrated additive antinociception in rats with a nerve ligation and in the formalin test, without apparent adverse side effects. In a model of neuropathic spinal cord injury pain, which is clinically difficult to treat, the combination of conantokin-G and omega-conotoxin MVIIA resulted in robust synergistic antinociception. These data suggest that a combination of these peptides may be analgesic across diverse clinical pains with limited untoward side effects, and particularly potent for reducing spinal cord injury pain.Neuropharmacology 11/2008; 56(2):556-63. · 4.11 Impact Factor
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ABSTRACT: The intrinsic electrical properties and the synaptic input-output relationships of neurons are governed by the action of voltage-dependent ion channels. The localization of specific populations of ion channels with distinct functional properties at discrete sites in neurons dramatically impacts excitability and synaptic transmission. Molecular cloning studies have revealed a large family of genes encoding voltage-dependent ion channel principal and auxiliary subunits, most of which are expressed in mammalian central neurons. Much recent effort has focused on determining which of these subunits coassemble into native neuronal channel complexes, and the cellular and subcellular distributions of these complexes, as a crucial step in understanding the contribution of these channels to specific aspects of neuronal function. Here we review progress made on recent studies aimed to determine the cellular and subcellular distribution of specific ion channel subunits in mammalian brain neurons using in situ hybridization and immunohistochemistry. We also discuss the repertoire of ion channel subunits in specific neuronal compartments and implications for neuronal physiology. Finally, we discuss the emerging mechanisms for determining the discrete subcellular distributions observed for many neuronal ion channels.Physiological Reviews 11/2008; 88(4):1407-47. · 30.17 Impact Factor