Submitted on August 8, 2005
Accepted on January 11, 2006
Alterations in dihydropyridine receptors in dystrophin-deficient cardiac muscle
Peter J Woolf1, Sai Lu1, Renee A Cornford-Nairn1, Michael Watson1, Xiao-Hui Xiao1, Sean M Holroyd1, Lindsay Brown2, and Andrew J Hoey1*
1 Centre for Biomedical Research, University of Southern Queensland, Toowoomba, Qld, Australia
2 Department of Physiology and Pharmacology, University of Queensland, Brisbane, Qld, Australia
* To whom correspondence should be addressed. E-mail: hoey{at}usq.edu.au.
The deficiency of dystrophin, an integral membrane stabilising protein, in the mdx mouse causes an elevation in intracellular calcium in all myocytes. One mechanism that could elicit increases in intracellular calcium is enhanced influx via the L-type calcium channels. This study investigated the effects of the dihydropyridines BayK 8644 and nifedipine and alterations in dihydropyridine receptors in dystrophin-deficient mdx hearts. A lower force of contraction and a reduced potency of extracellular calcium (P<0.05) was evident in mdx left atria. The dihydropyridine agonist Bay K 8644 and antagonist nifedipine had 2.7 and 1.9 fold lower potencies in contracting left atria (P<0.05). This corresponded with a 2.0 fold reduction in dihydropyridine receptor affinity evident from radioligand binding studies of mdx ventricular homogenates (P<0.05). Increased ventricular dihydropyridine receptor protein was evident from both radioligand binding studies and Western blots and was accompanied by increased mRNA levels (P<0.05). Patch clamp studies in isolated ventricular myocytes showed no change in L-type calcium current density, but revealed delayed channel inactivation (P<0.05). This study indicates that a deficiency of dystrophin leads to changes in dihydropyridine receptors and L-type calcium channel properties that may contribute to enhanced calcium influx. Increased influx is a potential mechanism for the calcium overload observed in dystrophin deficient cardiac muscle.
