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Prepublished online as a Blood First Edition Paper on June 21, 2002; DOI 10.1182/blood-2002-03-0723.
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Blood, 15 October 2002, Vol. 100, No. 8, pp. 2801-2811
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Expression and role of TRPC proteins in human platelets: evidence
that TRPC6 forms the store-independent calcium entry channel
Sheila R. Hassock,
Michael
X. Zhu,
Claudia Trost,
Veit Flockerzi, and
Kalwant S. Authi
From the Centre for Cardiovascular Biology and Medicine,
King's College London, New Hunt's House, Guy's Campus, London; the
Neurobiotechnology Centre, Ohio State University, Columbus; and the
Institut für Pharmakologie und Toxikologie der Universität
des Saarlandes, Homburg, Germany.
Store-operated Ca++ entry (SOCE) is thought to comprise
the major pathway for Ca++ entry in platelets. Recently, a
number of transient receptor potential (TRP) proteins, which have been
divided into 3 groups (TRPC, TRPM, and TRPV), have been suggested as
SOCE channels. We report the expression and function of TRPC proteins
in human platelets. TRPC6 is found at high levels and TRPC1 at low
levels. Using purified plasma (PM) and intracellular membranes (IM),
TRPC6 is found in the PM, but TRPC1 is localized to the IM. Using
Fura-2-loaded platelets, we report that, in line with TRPC6
expression, 1-oleoyl-2-acetyl-sn-glycerol (OAG) stimulated the entry of
Ca++ and Ba2+ independently of protein kinase
C. Thrombin also induced the entry of Ca++ and
Ba2+, but thapsigargin, which depletes the stores, induced
the entry of only Ca++. Thus, thrombin activated TRPC6 via
a SOCE-independent mechanism. In phosphorylation studies, we report
that neither TRPC6 nor TRPC1 was a substrate for tyrosine kinases.
TRPC6 was phosphorylated by cAMP-dependent protein kinase (cAMP-PK) and
associated with other cAMP-PK substrates. TRPC1 was not phosphorylated
by cAMP-PK but also associated with other substrates. Activation of
cAMP-PK inhibited Ca++ but not Ba2+ entry
induced by thrombin and neither Ca++ nor Ba2+
entry stimulated by OAG. These results suggest that TRPC6 is a
SOCE-independent, nonselective cation entry channel stimulated by
thrombin and OAG. TRPC6 is a substrate for cAMP-PK, although phosphorylation appears to not affect cation permeation. TRPC1 is
located in IM, suggesting a role at the level of the stores.
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Related Letter in Blood Online:
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TRP channels and calcium entry in human platelets
- Stewart O. Sage, Sharon L. Brownlow, Juan A. Rosado, Kalwant S. Authi, Sheila Hassock, Michael X. Zhu, Veit Flockerzi, and Claudia Trost
Blood 2002 100: 4245-4246.
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