PMID- 12069756
OWN - NLM
STAT- MEDLINE
DCOM- 20020815
LR  - 20191106
IS  - 1050-1738 (Print)
IS  - 1050-1738 (Linking)
VI  - 12
IP  - 4
DP  - 2002 May
TI  - Regulation of ryanodine receptors via macromolecular complexes: a novel role for 
      leucine/isoleucine zippers.
PG  - 166-70
AB  - Defective calcium (Ca(2+)) signaling, manifest as a loss of 
      excitation-contraction (EC) coupling gain in cardiac muscle, likely plays an 
      important role in the pathophysiology of human heart failure. The mechanism 
      underlying this loss of cardiac EC coupling gain involves altered regulation of 
      the cardiac ryanodine receptor (RyR2), the major sarcoplasmic reticulum Ca(2+) 
      release channel in the heart. This altered regulation of RyR2 is due, in part, to 
      hyperphosphorylation of the channel by cyclic adenosine monophosphate-dependent 
      protein kinase A (PKA). PKA phosphorylation of RyR2 is controlled by a 
      macromolecular signaling complex that targets PKA and two phosphatases (PP1 and 
      PP2A) to the channel. The targeting of PKA, PP1, and PP2A to RyR2 is dependent on 
      the binding of targeting proteins to the channel via highly conserved 
      leucine/isoleucine zippers (LIZs). Formation of an ion channel macromolecular 
      signaling complex is a novel role of LIZs. Recognition of this new function for 
      LIZ motifs has provided a road map for rapidly identifying components of the RyR2 
      macromolecular signaling complex that play a key role in regulating normal 
      cardiac physiology as part of the "fight or flight" response. The components of 
      the RyR2 macromolecular signaling complex are also novel targets for heart 
      failure and cardiac arrhythmia therapeutics.
FAU - Marks, Andrew R
AU  - Marks AR
AD  - Department of Medicine, Columbia University College of Physicians and Surgeons, 
      Center for Molecular Cardiology, New York 10032, USA. arm42@columbia.edu
FAU - Marx, Steven O
AU  - Marx SO
FAU - Reiken, Steven
AU  - Reiken S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PT  - Review
PL  - United States
TA  - Trends Cardiovasc Med
JT  - Trends in cardiovascular medicine
JID - 9108337
RN  - 0 (Macromolecular Substances)
RN  - 0 (Ryanodine Receptor Calcium Release Channel)
RN  - 04Y7590D77 (Isoleucine)
RN  - EC 5.2.1.- (Tacrolimus Binding Protein 1A)
SB  - IM
MH  - Animals
MH  - Heart/*physiology/physiopathology
MH  - Heart Failure/physiopathology
MH  - Humans
MH  - Isoleucine/*metabolism
MH  - Leucine Zippers/*physiology
MH  - Macromolecular Substances
MH  - Myocardium/metabolism
MH  - Ryanodine Receptor Calcium Release Channel/*metabolism
MH  - Tacrolimus Binding Protein 1A/metabolism
RF  - 39
EDAT- 2002/06/19 10:00
MHDA- 2002/08/16 10:01
CRDT- 2002/06/19 10:00
PHST- 2002/06/19 10:00 [pubmed]
PHST- 2002/08/16 10:01 [medline]
PHST- 2002/06/19 10:00 [entrez]
AID - S1050173802001561 [pii]
AID - 10.1016/s1050-1738(02)00156-1 [doi]
PST - ppublish
SO  - Trends Cardiovasc Med. 2002 May;12(4):166-70. doi: 10.1016/s1050-1738(02)00156-1.