PMID- 21666108
OWN - NLM
STAT- MEDLINE
DCOM- 20111101
LR  - 20210118
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Linking)
VI  - 301
IP  - 3
DP  - 2011 Sep
TI  - IRAG and novel PKG targeting in the cardiovascular system.
PG  - H672-82
LID - 10.1152/ajpheart.00198.2011 [doi]
AB  - Signaling by nitric oxide (NO) determines several cardiovascular functions 
      including blood pressure regulation, cardiac and smooth muscle hypertrophy, and 
      platelet function. NO stimulates the synthesis of cGMP by soluble guanylyl 
      cyclases and thereby activates cGMP-dependent protein kinases (PKGs), mediating 
      most of the cGMP functions. Hence, an elucidation of the PKG signaling cascade is 
      essential for the understanding of the (patho)physiological aspects of NO. 
      Several PKG signaling pathways were identified, meanwhile regulating the 
      intracellular calcium concentration, mediating calcium desensitization or 
      cytoskeletal rearrangement. During the last decade it emerged that the inositol 
      trisphosphate receptor-associated cGMP-kinase substrate (IRAG), an endoplasmic 
      reticulum-anchored 125-kDa membrane protein, is a main signal transducer of PKG 
      activity in the cardiovascular system. IRAG interacts specifically in a trimeric 
      complex with the PKG1beta isoform and the inositol 1,4,5-trisphosphate receptor I 
      and, upon phosphorylation, reduces the intracellular calcium release from the 
      intracellular stores. IRAG motifs for phosphorylation and for targeting to PKG1beta 
      and 1,4,5-trisphosphate receptor I were identified by several approaches. The 
      (patho)physiological functions for the regulation of smooth muscle contractility 
      and the inhibition of platelet activation were perceived. In this review, the 
      IRAG recognition, targeting, and function are summarized compared with PKG and 
      several PKG substrates in the cardiovascular system.
FAU - Schlossmann, Jens
AU  - Schlossmann J
AD  - Department of Pharmacology and Toxicology, Institute of Pharmacy, University of 
      Regensburg, Regensburg, Germany. jens.schlossmann@chemie.uni-regensburg.de
FAU - Desch, Matthias
AU  - Desch M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20110610
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Cardiovascular Agents)
RN  - 0 (IRAG1 protein, human)
RN  - 0 (Inositol 1,4,5-Trisphosphate Receptors)
RN  - 0 (Membrane Proteins)
RN  - 0 (Mrvi1 protein, mouse)
RN  - 0 (Phosphoproteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases)
RN  - H2D2X058MU (Cyclic GMP)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Cardiovascular Agents/*therapeutic use
MH  - Cardiovascular Diseases/*drug therapy/enzymology/physiopathology
MH  - Cardiovascular System/*drug effects/enzymology/physiopathology
MH  - Cyclic GMP/metabolism
MH  - Cyclic GMP-Dependent Protein Kinases/*antagonists & inhibitors/metabolism
MH  - Humans
MH  - Inositol 1,4,5-Trisphosphate Receptors/metabolism
MH  - Membrane Proteins/*metabolism
MH  - Molecular Sequence Data
MH  - Molecular Targeted Therapy
MH  - Nitric Oxide/metabolism
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation
MH  - Protein Kinase Inhibitors/*therapeutic use
MH  - Signal Transduction/*drug effects
EDAT- 2011/06/15 06:00
MHDA- 2011/11/02 06:00
CRDT- 2011/06/14 06:00
PHST- 2011/06/14 06:00 [entrez]
PHST- 2011/06/15 06:00 [pubmed]
PHST- 2011/11/02 06:00 [medline]
AID - ajpheart.00198.2011 [pii]
AID - 10.1152/ajpheart.00198.2011 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2011 Sep;301(3):H672-82. doi: 
      10.1152/ajpheart.00198.2011. Epub 2011 Jun 10.