The neuronal acid-sensing ion channels (ASICs) are postulated to detect mechanical stimuli through interactions with the intracellular cytoskeleton. Previous work has shown that a-actinins link ion channels in a Ca²⁺-dependent manner to the actin-skeleton and thereby regulate function. In order to test whether a-actinin may be a key element of an ASIC-cytoskeletal mechanosensory complex we heterologously co-expressed murine ASIC1a with neuronal actinin or dominant negative constructs of a-actinin. Overexpression of a-actinin increased the pH-sensitivity of ASIC1a. Co-expression of dominant negative actinin decreased proton sensitivity and reduced the rate of channel recovery from desensitization. Mutating a putative actinin-binding site in ASIC1a had the same effects on current properties as the dominant negative actinin. These findings suggest that a-actinins regulate the function of ASIC1a.