Diagram summarizing physiological regulation of ClC-1 function in active muscle fibers and the consequences for the excitability of the muscle fibers. The figure illustrates that Ca2+ released from SR triggers PKC-mediated ClC-1 inhibition. ClC-1 channels are also inhibited via lactate ions and intracellular acidification. The inhibitory action of reduced pHi on ClC-1 function is at least partly mediated via increased sensitivity for adenosine nucleotides of ClC-1 channels. ClC-1 inhibition represents an important mechanism for the muscle to preserve excitability during repeated action potential firing. Under conditions where ATP consumption exceeds ATP replenishing capacity, the adenosine nucleotides will decline, leading to formation of IMP. Given that IMP is inert on ClC-1 function, the decline in adenosine nucleotide can lead to marked activation of ClC-1. Inhibitory current through ClC-1 channels will thereby increase drastically, and this can shut off muscle excitability and possibly contribute to fatigue.
