PMID- 10087910
OWN - NLM
STAT- MEDLINE
DCOM- 19990415
LR  - 20191103
IS  - 0303-4240 (Print)
IS  - 0303-4240 (Linking)
VI  - 134
DP  - 1999
TI  - Pharmacomechanical coupling: the role of calcium, G-proteins, kinases and
      phosphatases.
PG  - 201-34
AB  - The concept of pharmacomechanical coupling, introduced 30 years ago to account
      for physiological mechanisms that can regulate contraction of smooth muscle
      independently of the membrane potential, has since been transformed from a
      definition into what we now recognize as a complex of well-defined, molecular
      mechanisms. The release of Ca2+ from the SR by a chemical messenger, InsP3, is
      well known to be initiated not by depolarization, but by agonist-receptor
      interaction. Furthermore, this G-protein-coupled phosphatidylinositol cascade,
      one of many processes covered by the umbrella of pharmacomechanical coupling, is 
      part of complex and general signal transduction mechanisms also operating in many
      non-muscle cells of diverse organisms. It is also clear that, although the major 
      contractile regulatory mechanism of smooth muscle,
      phosphorylation/dephosphorylation of MLC20, is [Ca2+]-dependent, the activity of 
      both the kinase and the phosphatase can also be modulated independently of
      [Ca2+]i. Sensitization to Ca2+ is attributed to inhibition of SMPP-1M, a process 
      most likely dominated by activation of the monomeric GTP-binding protein RhoA
      that, in turn, activates Rho-kinase that phosphorylates the regulatory subunit of
      SMPP-1M and inhibits its myosin phosphatase activity. It is likely that the tonic
      phase of contraction activated by a variety of excitatory agonists is, at least
      in part, mediated by this Ca(2+)-sensitizing mechanism. Desensitization to Ca2+
      can occur either through inhibitory phosphorylation of MLCK by other kinases or
      autophosphorylation and by activation of SMPP-1M by cyclic nucleotide-activated
      kinases, probably involving phosphorylation of a phosphatase activator. Based on 
      our current understanding of the complexity of the many cross-talking signal
      transduction mechanisms that operate in cells, it is likely that, in the future, 
      our current concepts will be refined, additional mechanisms of pharmacomechanical
      coupling will be recognized, and those contributing to the pathologenesis
      diseases, such as hypertension and asthma, will be identified.
FAU - Somlyo, A P
AU  - Somlyo AP
AD  - Department of Molecular Physiology and Biological Physics, University of
      Virginia, Charlottesville 22906-0011, USA.
FAU - Wu, X
AU  - Wu X
FAU - Walker, L A
AU  - Walker LA
FAU - Somlyo, A V
AU  - Somlyo AV
LA  - eng
GR  - P01-HL19242/HL/NHLBI NIH HHS/United States
GR  - P01-HL48807/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PT  - Review
PL  - Germany
TA  - Rev Physiol Biochem Pharmacol
JT  - Reviews of physiology, biochemistry and pharmacology
JID - 0434624
RN  - EC 2.7.- (Phosphotransferases)
RN  - EC 3.1.3.2 (Phosphoric Monoester Hydrolases)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Calcium/*physiology
MH  - GTP-Binding Proteins/*physiology
MH  - Humans
MH  - Muscle Contraction/physiology
MH  - Muscle, Smooth/*enzymology/*physiology
MH  - Phosphoric Monoester Hydrolases/*physiology
MH  - Phosphotransferases/*physiology
MH  - Signal Transduction/physiology
RF  - 169
EDAT- 1999/03/24 00:00
MHDA- 1999/03/24 00:01
CRDT- 1999/03/24 00:00
PHST- 1999/03/24 00:00 [pubmed]
PHST- 1999/03/24 00:01 [medline]
PHST- 1999/03/24 00:00 [entrez]
AID - 10.1007/3-540-64753-8_5 [doi]
PST - ppublish
SO  - Rev Physiol Biochem Pharmacol. 1999;134:201-34. doi: 10.1007/3-540-64753-8_5.