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

Abstract

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