This study evaluates episodic ataxia type 2 (EA2) stressinduced bouts of ataxia, vertigo, and dystonia. Most patients with EA2 are heterozygous for protein-truncating mutations in the โฃ1A subunit of the P/Q calcium channel. We hypothesized that dominant inheritance in EA2 arises because of a dominant negative effect of loss-of-function โฃ1A mutations on P/Q currents. We found that, when co-expressed with full-length subunits, โฃ1A truncations reduce P/Q current density in cultured cells, provided the truncation is distal to the โฃ-โค interaction domain. We found that mice heterozygous for a targeted disruption in the gene encoding โฃ1A (cacna1a ex13ฯฉ/ฯช ) express a truncated โฃ1A subunit, and have 50% reduced P/Q currents, but are neurologically normal. We hypothesized that cacna1a ex13ฯฉ/ฯช mice would exhibit stress-induced episodes of motor impairment. Administration of caffeine or mild restraint stress reproducibly induced focal dystonia, ataxia, and impaired rotorod performance, and the effect lasted 1-2 hours, reminiscent of EA2. These results suggest that EA2 arises from the dominant effects of truncated โฃ1A subunits that compete with full-length subunits for channel assembly, causing reduced native P/Q currents and susceptibility to stress-induced episodes of ataxia and dystonia. Study supported by NIH NS38332.