N-type calcium channels are w-conotoxin (w-Cg Tx)-sensitive, voltage-dependent ion channels involved in the control of neurotransmitter release from neurons. Multiple subtypes of voltage-dependent calcium channel complexes exist, and it is the [alpha.sub. 1] submit of the complex that forms the pore through which calcium enters the cell. The primary structures of human neuronal calcium channel [alpha.sub.1B] submits were enters the cell. The primary structures of human neuronal calcium channel [alpha.sub.1B] subunits were deduced by the characterization of overlapping complementary DNAs. Two forms ([alpha.sub.1B-1] and [alpha.sub.1B-2]) were identified in human neuroblastoma (IMR32) cells and in the central nervous systems, but not in skeletal muscle or aorta tissues. The [alpha.sub.1B-1] subunit directs the recombinant expression of N-type calcium channel activity when it is transiently co-expressed with human neuronal [Beta.sub.2] and [alpha.sub.2b] subunits in mammalian HEK293 cells. The recombinant channel was irreversibly blocked by w-Cg Tx but was insensitive to dihydropyrodines. The [alpha.sub.1B-1] [alpha.sub.2b] [Beta.sub.2-] transfected cells displayed a single class of saturable, high-affinity (dissociation constant = 55 pM) w-Cg Tx binding sites. Co-expression of the [Beta.sub.2} subunit was necessary for N-Type channel activity, whereas the [alpha.sub.2b] subunit appeared to modulate the expression of the channel. The heterogeneity of [alpha.sub.1B] subunits, along with the heterogeneity of [alpha.sub.2] and [Beta] subunits, is consistent with multiple, biophysically distinct N-type calcium channels.
Voltage-dependent Ca. sup.2+] channels are multisubunit complexes through which extracellular [Ca.sup.2+] enters excitable cells. In rabbit skeletal muscle, for tightly coupled subunits, [alpha.sub.1], [alpha.sub.2], [Beta], and [gamma], make up the channel complex. The primary structure of each subunit has been determined and [alpha.sub.1], [alpha.sub.2], and [Beta] cDNAs have been used to characterize transcripts expressed in other tissues. The [alpha.sub.1] and [Beta] subunits are each encoded by a gene family, including at least five distinct genes for [alpha.sub.1] subunits and three genes for [Beta] subunits[3-6]. Primary transcripts of each of the [alpha.sub.1] genes, the [alpha.sub.2] gene, and two of the [Beta] genes have been shown to yield multiple, structurally distinct, subunits by means of differential processing [6-9]. Expression studies have shown that the [alpha.sub.1] subunits forms the pore through which [Ca.sup.2+] enters the cell [10, 11].
On the basis of biophysical and pharmacological characteristics, three subtypes of neuronal, high-voltage-activated [Ca.sup.2+] channels (L-, N-, and P-type) have been proposed. These high-voltage-activated subtypes are most readily distinguished pharmacologically. The neuronal L-Type channel is dihydropyradine (DHP)-sensitive and, in some cases, reversibly blocked by w-conotoxin (w-CgTX)[12, 13], the N-type channel is DHP-insensitive and irreversibly blocked by w-CgTx, and the P-type channel is both DHP- and w-CgTx-insensitive but is sensitive to toxins in venom from funnel web spiders. Recently, recombinant expression of neuronal [Ca.sup.2+] channels was used to identify a high-voltage-activated, DHP,sensitive [Ca.sup.2+] channel that was reversibly blocked by w-CgTx (classified as an L-Type channel)  and a DHP-, w-CgTx-sensitive [Ca.sup.2+] channel (possibly a P-type channel). Co-expression of [alpha.sub.1] and [Beta] subunits is necessary for substantial functional expression of both [Ca.sup.2+] channel subtypes, whereas addition of an [alpha.sub.2] subunit increases the magnitude of the functional response.
Much evidence indicates that...
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