A glutamate-to-lysine substitution at position 1014 within the selectivity filter of the skeletal muscle L-type Ca2+ channel (CaV1.1) abolishes Ca2+ flux through the channel pore. Mice engineered to exclusively express the mutant channel display accelerated muscle fatigue, changes in muscle composition, and altered metabolism relative to wildtype littermates. By contrast, mice expressing another mutant CaV1.1 channel that is impermeable to Ca2+ (CaV1.1 N617D) have shown no detectable phenotypic differences from wildtype mice to date. The major biophysical difference between the CaV1.1 E1014K and CaV1.1 N617D mutants elucidated thus far is that the former channel conducts robust Na+ and Cs+ currents in patch-clamp experiments, but neither of these monovalent conductances seems to be of relevance in vivo Thus, the basis for the different phenotypes of these mutants has remained enigmatic. We now show that CaV1.1 E1014K readily conducts 1,4-dihydropyridine-sensitive K+ currents at depolarizing test potentials, whereas CaV1.1 N617D does not. Our observations, coupled with a large body of work by others regarding the role of K+ accumulation in muscle fatigue, raise the possibility that the introduction of an additional K+ flux from the myoplasm into the transverse-tubule lumen accelerates the onset of fatigue and precipitates the metabolic changes observed in CaV1.1 E1014K muscle. These results, highlighting an unexpected consequence of a channel mutation, may help define the complex mechanisms underlying skeletal muscle fatigue and related dysfunctions.