| Literature References | 1. BITO, H., DEISSEROTH, K. AND TSIEN, R.
Ca2+-dependent regulation in neuronal gene expression.
CURR.OPIN.NEUROBIOL. 7 419-429 (1997).
2. DUNLAP, K., LEUBKE, J. AND TURNER, T.
Exocytotic calcium channels in mammalian central neurons.
TRENDS NEUROSCI. 18 89-98 (1995).
3. AHLIJANIAN, M., WESTENBROEK, R. AND CATTERALL, W.
Subunit structure and localization of dihydropyridine-sensitive calcium
channels in mammalian brain, spinal cord, and retina.
NEURON 4 819-832 (1990).
4. WITCHER, D., DE WAARD, M., SAKAMOTO, J., FRANZINI-ARMSTRONG, C.,
PRAGNELL, M., KAHL, S. AND CAMPBELL, K.
Subunit identification and reconstitution of the N-type Ca2+ channel complex
purified from brain.
SCIENCE 261 486-489 (1993).
5. BURGESS, D., GEFRIDES, L., FOREMAN, P. AND NOEBELS, J.
A cluster of three novel Ca2+ channel gamma subunit genes on chromosome
19q13.4: evolution and expression profile of the gamma subunit gene family.
GENOMICS 71 339-350 (2001).
6. LETTS, V., FELIX, R., BIDDLECOME, G., ARIKKATH, J., MAHAFFEY, C.,
VALENZULA, A., BARTLETT, F, MORI, Y., CAMPBELL, K. AND FRANKEL, W.
The mouse stargazer gene encodes a neuronal Ca(2+)-channel gamma subunit.
NAT.GENET. 19 340-347 (1998).
7. CHEN, L., CHETKOVICH, D., PETRALLA, R., SWEENEY, N., KAWASKI, Y.,
WENTHOLD, R., BREDT, D. AND NICOLI, R.
Stargazin regulates synaptic targeting of AMPA receptors by two distinct
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NATURE 408 936-943 (2000).
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| Documentation | Voltage-dependent calcium channels are a diverse family of proteins that
encompass a variety of biological functions, including presynaptic
neurotransmitter release and protein signalling within the cell [1,2]. The
high voltage-activated channels (L-, N-, P-, Q- and R-type channels)
comprise the alpha-1 subunit, which creates the pore for the import of
extracellular calcium ions [2]. The activity of this pore is modulated by
four tightly-coupled subunits: an intracellular beta subunit; a
transmembrane (TM) gamma subunit; and a disulphide-linked complex of alpha-2
and delta subunits, which are proteolytically cleaved from the same gene
product [3,4].
The voltage-dependent calcium channel gamma (VDCCG) subunit family consists
of at least 8 members, which share a number of common structural features
[5]. Each member is predicted to possess four TM domains, with intracellular
N- and C- termini. The first extracellular loop contains a highly conserved
N-glycosylation site and a pair of conserved cysteine residues. The
C-terminal seven residues of VDCCG-2, -3, -4 and -8 are also conserved and
contain a consensus site for phosphorylation by cAMP and cGMP-dependent
protein kinases, and a target site for binding by PDZ domain proteins [5].
The VDCCG-2 subunit (also known as stargazin) was isolated by identifying
the locus of the genetic disruption in the epileptic mouse mutant line
known as stargazer [6]. VDCCG-2 subunits are brain specific and enriched in
synaptic plasma membranes. In vitro studies using recombinant P/Q-type
calcium channels show that VDCCG-2 subunit expression increases steady-state
channel inactivation, leading to the suggestion that, in stargazer mutants,
inappropriate calcium entry may contribute to the seizure phenotype [6].
VDCCG-2 subunits are also implicated in cellular trafficking. They interact
with ionotropic glutamate AMPA receptor subunits, a process that has been
shown to be essential in delivering functional AMPA receptors to the surface
membranes of cerebellar granule cells [7]. In addition, VDCCG-2 subunits
are capable of associating with PDZ proteins, such as PSD-95, through their
C-terminal PDZ binding domains. This interaction is required to target AMPA
receptors to cerebellar synapses [7].
VDCCGAMMA2 is a 3-element fingerprint that provides a signature for the
voltage-dependent calcium channel gamma-2 subunit proteins. The fingerprint
was derived from an initial alignment of 3 sequences: the motifs were drawn
from conserved regions in the C-terminal portion of the alignment, focusing
on those sections that characterise the VDCCG-2 subunits but distinguish
them from other family members - motifs 1, 2 and 3 all lie within the C-
terminal cytoplasmic tail region. A single iteration on SPTR39.22_17.3f was
required to reach convergence, no further sequences being identified beyond
the starting set.
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