| Literature References | 1. WILLIAMS, M.E., BRUST. P.F., FELDMAN, D.H., PATTHI, S., SIMERSON, S.,
MAROUFI, A., MCCUE, A.F., VELICELBI, G., ELLIS, S.B. AND HARPOLD, M.M.
Structure and functional expression of an omega-conotoxin sensitive human
N-type calcium channel.
SCIENCE 257 389-395 (1992).
2. MORI, Y., FRIEDRICH, T., KIM, MS., MIKAMI, A., NAKAI, J., RUTH, P.,
BOSSE, E., HOFMANN, F., FLOCKERZI, V., FURUICHI, T., MIKOSHIBA, K.,
IMOTO, K., TANABE, T. AND NUMA, S.
Primary structure and functional expression from complementary DNA of a
brain calcium channel.
NATURE 350 398-402 (1991).
3. ASHCROFT, F.M.
Voltage-gated Ca2+ channels.
IN ION CHANNELS AND DISEASE, ACADEMIC PRESS, 2000, PP.161-183.
4. KOCH, W.J., ELLINOR, P.T. AND SCHWARTZ, A.
cDNA cloning of a dihydropyridine-sensitive calcium channel from rat aorta -
evidence for the existence of alternatively spliced forms.
J.BIOL.CHEM. 265(29) 17786-17791 (1990).
5. LUEBKE, J.I., DUNLAP, K. AND TURNER, T.J.
Multiple calcium channel types control glutamatergic synaptic transmission
in the hippocampus.
NEURON 11 895-902 (1993).
6. TURNER, T.J., ADAMS, M.E. AND DUNLAP, K.
Multiple Ca2+ channel types coexist to regulate synaptosomal
neurotransmitter release.
PROC.NATL.ACAD.SCI.U.S.A. 90 9518-9522 (1993).
7. HIRNING, L.D., FOX, A.P., MCCLESKEY, E.W., OLIVERA, B.M., THAYER, S.A.,
MILLER, R.J. AND TSIEN, R.E.
Dominant role of N-type Ca2+ channels in evoked release of norepinephrine
from sympathetic neurons.
SCIENCE 239 57-61 (1988).
|
| Documentation | Calcium channel proteins are involved in the control of neurotransmitter
release from neurons [1], and play an important role in the regulation of a
variety of cellular functions, including membrane excitability, muscle
contraction and synaptic transmission [2]. Voltage-gated calcium channels
are classified as T, L, N, P, Q and R, and are distinguished by their
sensitivity to pharmacological blocks, single-channel conductance kinetics,
and voltage-dependence. On the basis of their voltage activation
properties, the voltage-gated calcium classes can be further divided into
two broad groups: the low (T-type) and high (L, N, P, Q and R-type)
threshold-activated channels [3].
Generally, the channel proteins are composed of 4 tightly-coupled subunits
(alpha-1, alpha-2, beta and gamma), the alpha-1 subunit from each creating
the pore for the import of extracellular calcium ions. The alpha-1 subunit
shares sequence characteristics with all voltage-dependent cation channels,
and exploits the same 6-helix bundle structural motif - in both sodium and
calcium channels, this motif is repeated 4 times within the sequence to give
a 24-helix bundle. Within each of these repeats, 5 of the transmembrane (TM)
segments (S1, S2, S3, S5, S6) are hydrophobic and one is positively charged
(S4) - the latter is characterised by charged amino acids at very third
position, and probably represents the voltage-sensor.
Several genes encoding alpha-1 subunits have been identified, each forming
a distinct electrophysiological channel [4]. N-type calcium channels are
composed from alpha-1B subunits. Experiments employing CTX have demonstrated
the physiological importance of the N-type calcium channels in the nervous
system, where they have a significant developmental role in the migration
of immature neurons before the establishment of their synaptic circuit. In
peripheral neurons, such as autonomic neurons, motor neurons and spinal
cord neurons, they have also been shown to be critically involved in the
release of neurotransmitters, including glutamate [5], gamma-amino-butyric
acid, acetylcholine, dopamine [6] and norepinephrine [7].
NVDCCALPHA1 is a 7-element fingerprint that provides a signature for the
N-type voltage-dependent calcium channel alpha-1 subunit. The fingerprint
was derived from an initial alignment of 5 sequences: the motifs were drawn
from conserved regions spanning the full alignment length: motif 1 lies in
the extracellular region between TM domains 5 and 6 of repeat I; motifs 2-6
encode the cytoplasmic region between the sixth TM domain of repeat II and
TM domain 1 of repeat III; and motif 7 resides in the cytoplasmic C-terminus.
Two iterations on SPTR40_18f were required to reach convergence, at which
point a true set comprising 15 sequences was identified.
|