PMID- 1320000
OWN - NLM
STAT- MEDLINE
DCOM- 19920806
LR  - 20210210
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 267
IP  - 18
DP  - 1992 Jun 25
TI  - Thapsigargin inhibits contraction and Ca2+ transient in cardiac cells by specific 
      inhibition of the sarcoplasmic reticulum Ca2+ pump.
PG  - 12545-51
AB  - Regulation of the level of ionized calcium, [Ca2+]i, is critical for its use as 
      an important intracellular signal. In cardiac and skeletal muscle the control of 
      fluctuations of [Ca2+]i depend on sarcolemmal and sarcoplasmic reticulum ion 
      channels and transporters. We have investigated the sesquiterpine lactone, 
      thapsigargin (TG), because of its reported action to alter cellular calcium 
      regulation in diverse cell types, including striated muscle cells. We have 
      combined biochemical and physiological methods at the cellular level to determine 
      the site of action of this agent, its specificity, and its cellular effects. 
      Using a patch-clamp method in whole cell configuration while measuring [Ca2+]i 
      with Indo-1 salt, we find that TG (100 nM) largely blocks the contraction and the 
      [Ca2+]i transient in rat ventricular myocytes. Analysis of these data indicate 
      that no sarcolemmal current or transport system is directly altered by TG, 
      although indirect [Ca2+]i-dependent processes are affected. In permeabilized 
      myocytes, TG blocked oxalate-stimulated calcium uptake (half-maximal effect at 10 
      nM) into the SR. However, TG (100 microM) had no effect on Ca(2+)-induced 
      Ca(2+)-release in purified muscle (ryanodine-receptor enriched) vesicles while 
      clearly blocking Ca(2+)-ATPase activity in purified (longitudinal SR) vesicles. 
      We conclude that in striated muscle TG markedly alters calcium metabolism and 
      thus alters contractile function only by its direct action on the Ca(2+)-ATPase.
FAU - Kirby, M S
AU  - Kirby MS
AD  - Department of Biological Chemistry, University of Maryland School of Medicine, 
      Baltimore 21201.
FAU - Sagara, Y
AU  - Sagara Y
FAU - Gaa, S
AU  - Gaa S
FAU - Inesi, G
AU  - Inesi G
FAU - Lederer, W J
AU  - Lederer WJ
FAU - Rogers, T B
AU  - Rogers TB
LA  - eng
GR  - HL25765/HL/NHLBI NIH HHS/United States
GR  - HL28131/HL/NHLBI NIH HHS/United States
GR  - HL36974/HL/NHLBI NIH HHS/United States
GR  - etc.
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Ion Pumps)
RN  - 0 (Oxalates)
RN  - 0 (Terpenes)
RN  - 67526-95-8 (Thapsigargin)
RN  - EC 7.2.2.10 (Calcium-Transporting ATPases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Calcium/*metabolism
MH  - Calcium-Transporting ATPases/antagonists & inhibitors
MH  - Cell Membrane Permeability
MH  - Cells, Cultured
MH  - Culture Techniques
MH  - Electric Conductivity
MH  - Heart/drug effects
MH  - Ion Pumps/*drug effects
MH  - Kinetics
MH  - Myocardial Contraction/*drug effects
MH  - Myocardium/cytology/*metabolism
MH  - Oxalates/pharmacology
MH  - Rats
MH  - Rats, Inbred Strains
MH  - Sarcoplasmic Reticulum/drug effects/enzymology/*metabolism
MH  - Terpenes/*pharmacology
MH  - Thapsigargin
EDAT- 1992/06/25 00:00
MHDA- 1992/06/25 00:01
CRDT- 1992/06/25 00:00
PHST- 1992/06/25 00:00 [pubmed]
PHST- 1992/06/25 00:01 [medline]
PHST- 1992/06/25 00:00 [entrez]
AID - S0021-9258(18)42311-3 [pii]
PST - ppublish
SO  - J Biol Chem. 1992 Jun 25;267(18):12545-51.