Store-operated Ca(2+) entry in platelets occurs independently of transient receptor potential (TRP) C1.
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 store-operated 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.
Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Zinklesweg 10, 97078, Würzburg, Germany.
David
D
Varga-Szabo
Kalwant S
KS
Authi
Attila
A
Braun
Markus
M
Bender
Archana
A
Ambily
Sheila R
SR
Hassock
Thomas
T
Gudermann
Alexander
A
Dietrich
Bernhard
B
Nieswandt
D000818:Animals; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000097:blood*; D020013:Calcium Signaling; D002712:Chlorides; D004195:Disease Models, Animal; D005290:Ferric Compounds; D006801:Humans; D008565:Membrane Proteins / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000097:blood; D015539:Platelet Activation; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D013927:Thrombosis / Q000097:blood / Q000139:chemically induced; D013997:Time Factors
D002712:Chlorides; D005290:Ferric Compounds; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D002118:Calcium; C024555:ferric chloride