Ecto-ATPase activity of alpha-sarcoglycan (adhalin)

alpha-Sarcoglycan is a component of the sarcoglycan complex of dystrophin-a ssociated proteins. Mutations of any of the sarcoglycan genes cause specifi c forms of muscular dystrophies, collectively termed sarcoglycanopathies. I mportantly, a deficiency of any specific sarcoglycan affects the expression of the others. Thus, it appears that the lack of sarcoglycans deprives the muscle cell of an essential, yet unknown function. In the present study, w e provide evidence for an ecto-ATPase activity of alpha-sarcoglycan. alpha- Sarcoglycan binds ATP in a Mg2+-dependent and Ca2+-independent manner. The binding is inhibited by 3'-O-(4-benzoyl)benzoyl ATP and ADP, Sequence analy sis reveals the existence of a consensus site for nucleotide binding in the extracellular domain of the protein, An antibody against this sequence inh ibits the binding of ATP, A dystrophin dystrophin-associated protein prepar ation demonstrates a Mg-ATPase activity that is inhibited by the antibody b ut not by inhibitors of endo-ATPases. In addition, we demonstrate the prese nce in the sarcolemmal membrane of a P2X-type purinergic receptor. These da ta suggest that alpha-sarcoglycan may modulate the activity of P2X receptor s by buffering the extracellular ATP concentration. The absence of a-sarcog lycan in sarcoglycanopathies leaves elevated the concentration of extracell ular ATP and the persistent activation of P2X receptors, leading to intrace llular Ca2+ overload and muscle fiber death.