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

• Published in: American journal of physiology. Heart and circulatory physiology 2005-03, Vol.57 (3), p.H1193-H1202
• Main Authors: GUANGMAO CHENG, FEI QIAO, GALLIEN, Thomas N, KUPPUSWAMY, Dhandapani, COOPER, George IV
• Format: Article
• Language: English
• Subjects: Adults; Biological and medical sciences; Cells; Fundamental and applied biological sciences. Psychology; Heart; Heart failure; Vertebrates: cardiovascular system
• ISSN: 0363-6135; 1522-1539

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. [3H]CGP-12177 was used as a beta-AR ligand, and feline cardiocytes were isolated and infected with adenovirus containing MAP4 (AdMAP4) or beta-galactosidase (Ad[beta]-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 Ad[beta]-gal cardiocytes; however, after agonist withdrawal, the cell surface beta-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, beta-AR agonist responsiveness of AdMAP4 cells was 47% less than that of Ad[beta]-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. [PUBLICATION ABSTRACT]