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

Gazes Cardiac Research Institute, Cardiology Division, Medical University of South Carolina, and Department of Veterans Affairs Medical Center, Charleston, South Carolina

Submitted 3 February 2004 ; accepted in final form 27 October 2004

Decreased -adrenergic receptor (-AR) number occurs both in animal models of cardiac hypertrophy and failure and in patients. -AR recycling is an important mechanism for the -AR resensitization that maintains a normal complement of cell surface -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 -AR recycling in adult cardiocytes. [³H]CGP-12177 was used as a -AR ligand, and feline cardiocytes were isolated and infected with adenovirus containing MAP4 (AdMAP4) or -galactosidase (Ad-gal) cDNA. MAP4 decorated the microtubules extensively only in AdMAP4 cardiocytes. -AR agonist exposure reduced cell surface -AR number comparably in AdMAP4 and Ad-gal cardiocytes; however, after agonist withdrawal, the cell surface -AR number recovered to 78.4 ± 2.9% of the pretreatment value in Ad-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, -AR agonist responsiveness of AdMAP4 cells was 47% less than that of Ad-gal cells. We conclude that MAP4 microtubule decoration interferes with -AR recycling and that this may be one mechanism for -AR downregulation in heart failure.

myocardium; hypertrophy; tubulin; adenovirus

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				G. Cheng, M. R. Zile, M. Takahashi, C. F. Baicu, D. D. Bonnema, F. Cabral, D. R. Menick, and G. Cooper 4th A direct test of the hypothesis that increased microtubule network density contributes to contractile dysfunction of the hypertrophied heart Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2231 - H2241. [Abstract] [Full Text] [PDF]

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