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L-type (α_1C) calcium channels inactivate rapidly in response to localized elevation of intracellular Ca²⁺, providing negative Ca²⁺ feedback in a diverse array of biological contexts. The dominant Ca²⁺ sensor for such Ca²⁺-dependent inactivation has recently been identified as calmodulin, which appears to be constitutively tethered to the channel complex. This Ca²⁺ sensor induces channel inactivation by Ca²⁺-dependent CaM binding to an IQ-like motif situated on the carboxyl tail of α_1C. Apart from the IQ region, another crucial site for Ca²⁺ inactivation appears to be a consensus Ca²⁺-binding, EF-hand motif, located ∼100 amino acids upstream on the carboxyl terminus. However, the importance of this EF-hand motif for channel inactivation has become controversial since the original report from our lab implicating a critical role for this domain. Here, we demonstrate not only that the consensus EF hand is …