TRPC1, a human homolog of a Drosophila store-operated channel.

Abstract

In many vertebrate and invertebrate cells, inositol 1,4,5-trisphospate production induces a biphasic Ca2+ signal. Mobilization of Ca2+ from internal stores drives the initial burst. The second phase, referred to as storeoperated Ca2+ entry (formerly capacitative Ca2+ entry), occurs when depletion of intracellular Ca2+ pools activates a non-voltage-sensitive plasma membrane Ca2+ conductance. Despite the prevalence of store-operated Ca2+ entry, no vertebrate channel responsible for store-operated Ca2+ entry has been reported. trp (transient receptor potential), a Drosophila gene required in phototransduction, encodes the only known candidate for such a channel throughout phylogeny. In this report, we describe the molecular characterization of a human homolog of trp, TRPCI. TRPC1 (transient receptor potential channel-related protein 1) was 40%o identical to Drosophila TRP over most of the protein and lacked the charged residues in the S4 transmembrane region proposed to be required for the voltage sensor in many voltage-gated ion channels. TRPCI was expressed at the highest levels in the fetal brain and in the adult heart, brain, testis, and ovaries. Evidence is also presented that TRPC1 represents the archetype of a family of related human proteins. Several signaling mechanisms for store-operated Ca2+ entry have been proposed (for review, see refs. 1, 3-5, 11). In one model, a diffusible messenger is produced or released upon depletion of the intracellular Ca2+ pool, and this messenger then activates the plasma membrane Ca2+ channels (12). A second model suggests that emptying the intracellular Ca2+ stores causes a conformational change in the storage organelle and/or its surface proteins, such as the InsP3 receptor, which is transmitted to plasma membrane Ca2+ channels either by direct coupling or via the cytoskeleton (13,14). Despite the prevalence of store-operated Ca2+ entry, no vertebrate SOC gene has been identified. Elucidation of the mechanism responsible for store-operated Ca2+ entry would be considerably aided by cloning and characterizing the channels.

Expression of human TRPC genes in the megakaryocytic cell lines MEG01, DAMI and HEL

“…Northern blot analysis has previously demonstrated highlevel expression of TRPC1 in heart, brain, testes and ovary, and lower levels of TRPC1 transcripts in all other human tissues tested with the exception of liver [10,11]. However, homologous TRPC1 mRNA in mouse liver could be detected by RT-PCR analysis, suggesting that low levels of TRPC1 transcripts may also be found in human liver.…”

“…It therefore appears that all three human TRPC genes may be ubiquitously transcribed. Wes et al [10] have reported that the TRPC2 cDNA sequence contains a stop codon in a position corresponding to residue 690 in TRPC1 (Fig. 2) and may therefore represent an expressed pseudogene.…”

“…The identification of human genes encoding potential storeoperated ion channels [10] will now provide the opportunity to analyse the role of the corresponding proteins in various cell types. The finding that TRPC1A expressed in CHO cells can be activated by thapsigargin or IP 3 is strong evidence that these proteins play an important role in receptor mediated Ca 2+ entry.…”

“…These studies have led to the search for human homologues of TRP and TRPL proteins that may represent candidate plasma membrane Ca 2+ channels. Recently, two groups have reported two cDNA stretches coding for proteins termed TRPC1 [10] and Htrp-1 [11] whose primary structure shares approx. 37-40% sequence identity to TRP and TRPL.…”

Acrosome reaction: relevance of zona pellucida glycoproteins

“…36 Transient receptor potential homologues have also been located in human sperm. 37,38 In addition, members of soluble Nethyl maleimide-sensitive factor attachment protein receptor proteins present in the acrosome region of mammalian sperm may also facilitate calcium entry, thereby leading to the AR. 39,40 The high intracellular free calcium concentration together with DAG leads to membrane fusion and finally acrosomal exocytosis.…”