The molecular basis of the Ca2+ release activated calcium (CRAC) current has been discovered. In the current model ORAI1 functions as a plasma membrane channel activated by STIM1, a Ca2+ binding protein of the ER. ORAI1 can be inhibited by STIM2, a protein closely related to STIM1. The fact that a missense mutation in the ORAI1 gene causes a severe combined immune deficiency syndrome associated with a congenital myopathy emphasized its relevance. To study whether STIM and ORAI are involved in the abnormal Ca2+ regulation of mdx muscle we analyzed the gene expression of all known ORAI and STIM isoforms. Using TaqMan RT-PCR we found ORAI1, STIM1 and STIM2 to be expressed at substantial levels while the mRNAs of ORAI2 and 3 were hardly detectable. In all tested mdx muscles ORAI1 expression was not different from control. In mdx hindlimb muscles STIM1 expression was reduced to 35-25% of control while STIM2 mRNA levels were 3 to 7 fold increased. In mdx diaphragm the STIM1 mRNA was reduced to 5% of control level while STIM2 expression was normal. We presume that Ca2+ dependent gene regulation suppresses the transcription of the ORAI1 activator STIM1 and activates that of the inhibitor STIM2 in mdx muscle. The mechanism probably constitutes a negative feedback between cellular Ca2+ load and ORAI1- dependent Ca2+ entry in muscle fibres.