Store-operated Ca2+ entry in platelets occurs independently of transient receptor potential (TRP) C1

Abstract

Changes in [Ca 2+ ] i are a central step in platelet activation. In nonexcitable cells, receptor-mediated depletion of intracellular Ca 2+ stores triggers Ca 2+ entry through store-operated calcium (SOC) channels. Stromal interaction molecule 1 (STIM1) has been identified as an endoplasmic reticulum (ER)-resident Ca 2+ sensor that regulates storeoperated calcium entry (SOCE), but the identity of the SOC channel in platelets has been controversially debated. Some investigators proposed transient receptor potential (TRP) C1 to fulfil this function based on the observation that antibodies against the channel impaired SOCE in platelets. However, others could not detect TRPC1 in the plasma membrane of platelets and raised doubts about the specificity of the inhibiting anti-TRPC1 antibodies. To address the role of TRPC1 in SOCE in platelets, we analyzed mice lacking TRPC1. Platelets from these mice display fully intact SOCE and also otherwise unaltered calcium homeostasis compared to wild-type. Furthermore, platelet function in vitro and in vivo is not altered in the absence of TRPC1. Finally, studies on human platelets revealed that the presumably inhibitory anti-TRPC1 antibodies have no specific effect on SOCE and fail to bind to the protein. Together, these results provide evidence that SOCE in platelets is mediated by channels other than TRPC1.

Potentiation of the store-operated calcium entry (SOCE) induces phytohemagglutinin-activated Jurkat T cell apoptosis

“…This release causes in turn the opening of the Ca 2+ release activated Ca 2+ channels (CRAC channels) [3] of the plasma membrane, allowing a massive Ca 2+ influx known as store-operated Ca 2+ entry (SOCE), which is necessary for the T cell activation [4]. Thus, a sustained increase of the resting cytosolic calcium concentration ([Ca 2+ ] cyt ) must persist for at least 2 hours to induce the full T cell commitment [5][6][7].…”

“…Unfortunately 2-APB lacks specificity as it can also affect the function of various other Ca 2+ -transporting mechanisms. Depending on the concentration, 2-APB can inhibit IP 3 Rs, sarco-and endoplasmic Ca 2+ ATPase (SERCA) pumps, as well as some transient receptor potential (TRP) channels of the TRPC family [21][22][23][24][25] while opening some members of the TRPV family [26,27]. A few teams have already documented the synthesis of 2-APB analogues, but only with the purpose of developing more specific inhibitors [28][29][30][31][32].…”

Regulation of TRPC1 and TRPC4 Cation Channels Requires an α1-Syntrophin-dependent Complex in Skeletal Mouse Myotubes

“…Recently, the study of salivary gland cells from TRPC1 Ϫ/Ϫ mice showed that TRPC1 is necessary for store-operated currents in this tissue (11), whereas the analysis of platelets from TRPC1 Ϫ/Ϫ mice showed that store-operated calcium entry (SOCE) occurs independently of TRPC1 (12). Two other proteins, STIM1, a single transmembrane protein (stromal interaction protein 1) and Orai1, a four-transmem-brane domain protein, have emerged as components of the store-operated channels (13,14) and can interact with TRPC proteins in a heteromeric complex to confer responsiveness to store depletion in various cells (15)(16)(17).…”

The importance of calcium in the regulation of megakaryocyte function

“…19,20 However, whether or not TRPC1 is an additional candidate for SOCE is still a matter of debate. 21,23 Conversely, TRPC6 activation is completely independent of store depletion.24 Importantly, we demonstrated that SOCE was functionally activated in response to the emptying of the IP3-sensitive Ca 2+ reservoir. Specifically, passive depletion of the ER Ca 2+ content with CPA, led to the formation of a ternary molecular complex between STIM1, Orai1 and TRPC1 which is likely to be involved in SOCE.…”

“…In this regard, STIM1 and Orai1 proteins have been shown to be key players in human platelet SOCE during aggregation, 21,22 whereas TRPC involvement has been questioned. 23,24 Importantly, it has been demonstrated that SOCE plays a major role in mediating adhesion and motility onto ECM components of different cell types, including hematopoietic stem cells.9,25 Thus we hypothesized that purinergic signaling and SOCE may be responsible for Mk interaction with the ECM environment and consequent regulation of platelet production. Our results demonstrate that ADP induces both intracellular Ca 2+ mobilization and extracellular Ca 2+ inflow in human Mks, which in turn support the cytoskeletal reorganization responsible for cellular adhesion and migration and final proplatelet formation on ECM components that promote such a dynamic process, such as fibrinogen and fibronectin.…”