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Inhibition of beta-adrenergic receptor trafficking in adult cardiocytes by MAP4 decoration of microtubules.

Abstract
Decreased beta-adrenergic receptor (beta-AR) number occurs both in animal models of cardiac hypertrophy and failure and in patients. beta-AR recycling is an important mechanism for the beta-AR resensitization that maintains a normal complement of cell surface beta-ARs. We have shown that 1) in severe pressure overload cardiac hypertrophy, there is extensive microtubule-associated protein 4 (MAP4) decoration of a dense microtubule network; and 2) MAP4 microtubule decoration inhibits muscarinic acetylcholine receptor recycling in neuroblastoma cells. We asked here whether MAP4 microtubule decoration inhibits beta-AR recycling in adult cardiocytes. [(3)H]CGP-12177 was used as a beta-AR ligand, and feline cardiocytes were isolated and infected with adenovirus containing MAP4 (AdMAP4) or beta-galactosidase (Adbeta-gal) cDNA. MAP4 decorated the microtubules extensively only in AdMAP4 cardiocytes. beta-AR agonist exposure reduced cell surface beta-AR number comparably in AdMAP4 and Adbeta-gal cardiocytes; however, after agonist withdrawal, the cell surface beta-AR number recovered to 78.4 +/- 2.9% of the pretreatment value in Adbeta-gal cardiocytes but only to 56.8 +/- 1.4% in AdMAP4 cardiocytes (P < 0.01). This result was confirmed in cardiocytes isolated from transgenic mice having cardiac-restricted MAP4 overexpression. In functional terms of cAMP generation, beta-AR agonist responsiveness of AdMAP4 cells was 47% less than that of Adbeta-gal cells. We conclude that MAP4 microtubule decoration interferes with beta-AR recycling and that this may be one mechanism for beta-AR downregulation in heart failure.
AuthorsGuangmao Cheng, Fei Qiao, Thomas N Gallien, Dhandapani Kuppuswamy, George Cooper 4th
JournalAmerican journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 288 Issue 3 Pg. H1193-202 (Mar 2005) ISSN: 0363-6135 [Print] United States
PMID15528234 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Adrenergic beta-Agonists
  • Microtubule-Associated Proteins
  • Propanolamines
  • Receptors, Adrenergic, beta
  • Tritium
  • Cyclic AMP
  • CGP 12177
Topics
  • Adenoviridae (genetics)
  • Adrenergic beta-Agonists (metabolism, pharmacology)
  • Animals
  • Cats
  • Cells, Cultured
  • Cyclic AMP (metabolism)
  • Down-Regulation (physiology)
  • Female
  • Gene Expression
  • Gene Transfer Techniques
  • Heart Ventricles (cytology, metabolism)
  • Humans
  • Male
  • Mice
  • Microtubule-Associated Proteins (genetics, metabolism)
  • Microtubules (metabolism)
  • Myocardium (cytology, metabolism)
  • Myocytes, Cardiac (cytology, metabolism)
  • Propanolamines (metabolism, pharmacology)
  • Receptors, Adrenergic, beta (metabolism)
  • Tritium

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