Family 1.A.4 - The Transient Receptor Potential Ca2+ Channel Family
Family ID: 53367
The TRP-CC family has also been called the store-operated calcium
channel (SOC) family. The prototypical members include the Drosophila
retinal proteins TRP and TRPL (Montell and Rubin, 1989; Hardie
and Minke, 1993). SOC members of the family mediate the entry
of extracellular Ca2+ into cells in response to depletion of intracellular
Ca2+ stores (Clapham, 1996) and agonist stimulated production
of inositol-1,4,5 trisphosphate (IP3). One member of the TRP-CC
family, mammalian Htrp3, has been shown to form a tight complex
with the IP3 receptor (TC #1.A.3.2.1). This interaction is apparently
required for IP3 to stimulate Ca2+ release via Htrp3. The vanilloid
receptor subtype 1 (VR1), which is the receptor for capsaicin
(the "hot" ingredient in chili peppers) and serves as
a heat-activated ion channel in the pain pathway (Caterina et
al., 1997), is also a member of this family, and is activated
by cannabinoids (i.e., anandamide) and certain inflammatory metabolites
of arachidonate such as prostaglandin E2 (Olah et al., 2001).
The stretch-inhibitable non-selective cation channel (SIC) is
identical to the vanilloid receptor throughout all of its first
700 residues, but it exhibits a different sequence in its last
100 residues. VR1 and SIC transport monovalent cations as well
as Ca2+. VR1 is about 10x more permeable to Ca2+ than to monovalent
ions. Ca2+ overload probably causes cell death after chronic exposure
to capsaicin (McCleskey and Gold, 1999).
The proteins
of the TRP-CC family exhibit the same topological organization.
They consist of about 700-800 (VR1, SIC or ECaC) or 1300 (TRP
proteins) amino acyl residues with six transmembrane spanners
(TMSs) as well as a short hydrophobic "loop" region
between TMSs 5 and 6. This loop region may dip into the membrane
and contribute to the ion permeation pathway (Hardie and Minke,
1993). An aspartate residue in the P-loop may form a ring of negative
charges that modulate pore properties including ion selectivity
and inhibitory characteristics (García-Martínez
et al., 2000). VR1 forms homotetramers. In these respects, members
of the TRP-CC family resemble those of the VIC family although
homology cannot be established on the basis of sequence similarity.
However, when one member of the TRP-CC family, the IGF-regulated
Ca2+ channel of Mus musculus (TC #1.A.4.2.4), was PSI-BLASTED,
it retrieved a partial sequence of a Zea mays K+ channel protein
(887 aas; gbY07632) that is clearly a member of the VIC family.
The two homologous protein segments of 150 residues were 28% identical,
42% similar with a PSI-BLAST score (without iterations) of 2e6.
This observation further suggests a common origin for at least
certain domains in the TRP-CC and VIC families.
The amino
termini of TRP-CC proteins normally contain a proline-rich region
and one or more ankyrin domains. VR1, for example, exhibits three
such repeat domains in its amino terminal hydrophilic segment
(432 amino acids). It also has a hydrophilic C-terminus that lacks
recognizable motifs. The sequence similarity between VR1 and other
TRP-CC family proteins is within and adjacent to the sixth TMS,
including the hydrophobic "loop" region. Unlike other
TRP-CC family members, VR1 is not a SOC. Mammals appear to have
multiple VR1 homologues.
One member
of the TRP-CC family, TRP-PLIK (1862 aas; AF346629), has been
implicated in the regulation of cell division. It has an N-terminal
TRP-CC-like sequence and a C-terminal protein kinase-like sequence.
It was shown to autophosphorylate and exhibits an ATP phosphorylation-dependent,
non-selective, Ca2+-permeable, outward rectifying conductance
(Runnels et al., 2001). Another long homologue, Melastatin, is
associated with melanocytic tumor progression whereas another
homologue, MTR1, is associated with Beckwith-Wiedemann syndrome
and a predisposition for neoplasia. Each of these proteins may
be present in the cell as several splice variants.
