[1] Stanford Univ, Sch Med, Beckman Ctr B111A, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA
来源:
JOURNAL OF PHYSIOLOGY-LONDON
|
2002年
/
541卷
/
03期
关键词:
D O I:
10.1113/jphysiol.2001.016154
中图分类号:
Q189 [神经科学];
学科分类号:
071006 ;
摘要:
In addition to its homeostatic role of maintaining low resting levels of intracellular calcium ([Ca2+](i)), the plasma-membrane calcium-ATPase (PMCA) may actively contribute to the generation of complex Ca2+ signals. We have investigated the role of the PMCA in shaping Ca" signals in Jurkat human leukaemic T cells using single-cell voltage-clamp and calcium-imaging techniques. Crosslinking the T-cell receptor with the monoclonal antibody OKT3 induces a biphasic elevation in [Ca2+](i) consisting of a rapid overshoot to a level > I muM, followed by a slow decay to a plateau of similar to0.5 mum. A similar overshoot was triggered by a constant level of Ca2+ influx through calcium-release-activated Ca2+ (CRAC) channels in thapsigargin-treated cells, due to a delayed increase in the rate of Ca2+ clearance by the PMCA. Following a rise in [Ca2+](i), PMCA activity increased in two phases: a rapid increase followed by a further calcium-dependent increase of up to approximately fivefold over 10-60 s, termed modulation. After the return of [Ca2+](i) to baseline levels, the PMCA recovered slowly from modulation (tau similar to 4 min), effectively retaining a 'memory' of the previous [Ca2+](i) elevation. Using a Michaelis-Menten model with appropriate corrections for cytoplasmic Ca2+ buffering, we found that modulation extended the dynamic range of PMCA activity by increasing both the maximal pump rate and Ca" sensitivity (reduction of K-M). A simple flux model shows how pump modulation and its reversal produce the initial overshoot of the biphasic [Ca2+](i) response. The modulation of PNICA activity enhanced the stability of Ca2+ signalling by adjusting the efflux rate to match influx through CRAC channels, even at high [Ca2+](i) levels that saturate the transport sites and would otherwise render the cell defenceless against additional Ca2+ influx. At the same time, the delay in modulation enables small Ca2+ fluxes to transiently elevate [Ca2+](i), thus enhancing Ca2+ signalling dynamics.
机构:
Natl Univ La Plata, Fac Ciencias Med, UNLP CONICET La Plata, PAHO WHO Collaborating Ctr,CENEXA Ctr Endocrinol, RA-1900 La Plata, ArgentinaNatl Univ La Plata, Fac Ciencias Med, UNLP CONICET La Plata, PAHO WHO Collaborating Ctr,CENEXA Ctr Endocrinol, RA-1900 La Plata, Argentina
Alzugaray, Maria E.
Garcia, Maria E.
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Natl Univ La Plata, Fac Ciencias Med, UNLP CONICET La Plata, PAHO WHO Collaborating Ctr,CENEXA Ctr Endocrinol, RA-1900 La Plata, ArgentinaNatl Univ La Plata, Fac Ciencias Med, UNLP CONICET La Plata, PAHO WHO Collaborating Ctr,CENEXA Ctr Endocrinol, RA-1900 La Plata, Argentina
Garcia, Maria E.
Del Zotto, Hector H.
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Natl Univ La Plata, Fac Ciencias Med, UNLP CONICET La Plata, PAHO WHO Collaborating Ctr,CENEXA Ctr Endocrinol, RA-1900 La Plata, ArgentinaNatl Univ La Plata, Fac Ciencias Med, UNLP CONICET La Plata, PAHO WHO Collaborating Ctr,CENEXA Ctr Endocrinol, RA-1900 La Plata, Argentina
Del Zotto, Hector H.
Raschia, Maria A.
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Natl Univ La Plata, Fac Ciencias Med, UNLP CONICET La Plata, PAHO WHO Collaborating Ctr,CENEXA Ctr Endocrinol, RA-1900 La Plata, ArgentinaNatl Univ La Plata, Fac Ciencias Med, UNLP CONICET La Plata, PAHO WHO Collaborating Ctr,CENEXA Ctr Endocrinol, RA-1900 La Plata, Argentina
Raschia, Maria A.
Palomeque, Julieta
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Natl Univ La Plata, Fac Ciencias Med, UNLP CONICET La Plata, CIC, RA-1900 La Plata, ArgentinaNatl Univ La Plata, Fac Ciencias Med, UNLP CONICET La Plata, PAHO WHO Collaborating Ctr,CENEXA Ctr Endocrinol, RA-1900 La Plata, Argentina
Palomeque, Julieta
Rossi, Juan P. F. C.
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Fac Farm & Bioquim, Dept Quim Biol, IQUIFIB Inst Quim & Fisicoquim Biol UBA CONICET, Buenos Aires, DF, ArgentinaNatl Univ La Plata, Fac Ciencias Med, UNLP CONICET La Plata, PAHO WHO Collaborating Ctr,CENEXA Ctr Endocrinol, RA-1900 La Plata, Argentina
Rossi, Juan P. F. C.
Gagliardino, Juan J.
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Natl Univ La Plata, Fac Ciencias Med, UNLP CONICET La Plata, PAHO WHO Collaborating Ctr,CENEXA Ctr Endocrinol, RA-1900 La Plata, ArgentinaNatl Univ La Plata, Fac Ciencias Med, UNLP CONICET La Plata, PAHO WHO Collaborating Ctr,CENEXA Ctr Endocrinol, RA-1900 La Plata, Argentina
Gagliardino, Juan J.
Flores, Luis E.
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Natl Univ La Plata, Fac Ciencias Med, UNLP CONICET La Plata, PAHO WHO Collaborating Ctr,CENEXA Ctr Endocrinol, RA-1900 La Plata, ArgentinaNatl Univ La Plata, Fac Ciencias Med, UNLP CONICET La Plata, PAHO WHO Collaborating Ctr,CENEXA Ctr Endocrinol, RA-1900 La Plata, Argentina