A novel capacitative calcium entry channel expressed in excitable cells

Abstract

In addition to voltage-gated calcium influx, capacitative calcium entry (CCE) represents a major pathway for calcium entry into the cell. Here we report the structure, expression and functional properties of a novel CCE channel, TRP5. This channel is a member of a new subfamily of mammalian homologues of the Drosophila transient receptor potential (TRP) protein, now comprising TRP5 (also CCE2) and the structurally related CCE1 (also TRP4). Like TRP4, TRP5 forms ion channels mainly permeable for Ca 2⍣ which are not active under resting conditions but can be activated by manoeuvres known to deplete intracellular calcium stores. Accordingly, dialysis of TRP5-expressing cells with inositol-(1,4,5)-trisphosphate evokes inward rectifying currents which reversed polarity at potentials more positive than ⍣30 mV. Ca 2⍣ store depletion with thapsigargin induced TRP5-mediated calcium entry dependent on the concentration of extracellular calcium, as seen by dual wavelength fura-2 fluorescence ratio measurements. TRP5 transcripts are expressed almost exclusively in brain, where they are present in mitral cells of the olfactory bulb, in lateral cerebellar nuclei and, together with TRP4 transcripts, in CA1 pyramidal neurons of the hippocampus, indicating the presence of CCE channels in excitable cells and their participation in neuronal calcium homeostasis.

Formation of Novel TRPC Channels by Complex Subunit Interactions in Embryonic Brain

“…Whereas TRPC4 and TRPC5 were activated by an unknown PLC-dependent mechanism (8, 9), TRPC1 was characterized as a SOC (10). Other studies indicated that TRPC3, TRPC4, and TRPC5 might also contribute to SOCs activated by depletion of intracellular Ca 2ϩ stores (11)(12)(13)(14).Based on their structural similarity with voltage-dependent K ϩ channels, functional TRPC complexes are presumed to be tetramers. Many of the disparate results regarding TRPC function and regulation could be reconciled by assuming that TRPC subunits can assemble into heteromeric channels with diverse properties.…”

“…Whereas TRPC4 and TRPC5 were activated by an unknown PLC-dependent mechanism (8, 9), TRPC1 was characterized as a SOC (10). Other studies indicated that TRPC3, TRPC4, and TRPC5 might also contribute to SOCs activated by depletion of intracellular Ca 2ϩ stores (11)(12)(13)(14).…”

Regulation of TRPC6 Channel Activity by Tyrosine Phosphorylation

“…Recent investigations have extensively studied the regulation of TRPC channel activity. TRPC1, -4, and -5 appear to be activated through a store-operated mechanism (7)(8)(9). TRPC3 and TRPC1 are physically associated with IP 3 receptors (10 -13) and ryanodine receptors (14) and are activated when a gated conformational change in the IP 3 receptors or ryanodine receptors is sensed.…”

TRPC3: a versatile transducer molecule that serves integration and diversification of cellular signals

“…The initial hypothesis of TRPC species (canonical mammalian TRP homologs) representing the structural basis of the ubiquitous Ca 2+ entry pathway termed capacitative-(CCE) or store-operated Ca 2+ entry (SOCE), which replenishes cellular Ca 2+ stores after intracellular Ca 2+ mobilization, Zhu et al 1996;Zitt et al 1996;Philipp et al 1998), was questioned or contradicted in many follow-up studies (Zitt et al 1997;Sinkins et al 1998;Zhu et al 1998;McKay et al 2000;Schaefer et al 2000). The prominent approach used in these investigations was heterologous expression of a single TRPC species in cellular systems that have proven suitable for analysis of ion channel function.…”