Mutation S218L in the Ca V 2.1 ␣ 1 subunit of P/Q-type Ca 2؉ channels produces a severe clinical phenotype in which typical attacks of familial hemiplegic migraine (FHM) triggered by minor head trauma are followed, after a lucid interval, by deep (even fatal) coma and long lasting severe cerebral edema. We investigated the functional consequences of this mutation on human Ca V 2.1 channels expressed in human embryonic kidney 293 cells and in neurons from Ca V 2.1 ␣ 1 ؊/؊ mice by combining single channel and whole cell patch clamp recordings. Mutation S218L produced a shift to lower voltages of the single channel activation curve and a consequent increase of both single channel and whole cell Ba 2؉ influx in both neurons and human embryonic kidney 293 cells. Compared with the other FHM-1 mutants, the S218L shows one of the largest gains of function, especially for small depolarizations, which are insufficient to open the wild-type channel. S218L channels open at voltages close to the resting potential of many neurons. Moreover, the S218L mutation has unique effects on the kinetics of inactivation of the channel because it introduces a large component of current that inactivates very slowly, and it increases the rate of recovery from inactivation. During long depolarizations at voltages that are attained during cortical spreading depression, the extent of inactivation of the S218L channel is considerably smaller than that of the wild-type channel. We discuss how the unique combination of a particularly slow inactivation during cortical spreading depression and a particularly low threshold of channel activation might lead to delayed severe cerebral edema and coma after minor head trauma. Familial hemiplegic migraine (FHM)1 is a rare autosomal dominant subtype of migraine with aura. Apart from the characteristic transient hemiparesis, typical attacks of FHM are similar to those of the common migraine with aura (1). Some FHM patients also show atypical attacks, either with a prolonged aura or with signs of diffuse encephalopathy; moreover, 20% of FHM families show permanent cerebellar symptoms (2). In about half of the families, FHM is caused by missense mutations in the CACNA1A gene, encoding the pore-forming ␣ 1 subunit of voltage-gated neuronal Ca V 2.1 (P/Q-type) Ca 2ϩ channels (FHM-1) (3). Ca V 2.1 channels are located at presynaptic terminals and somatodendritic membranes (4) and are expressed in all brain structures that have been implicated in the pathogenesis of migraine (5). They play a prominent role in controlling neurotransmitter release (6) and also exert postsynaptic effects, such as on neuronal excitability (7).17 different missense mutations have been associated with FHM-1 (8 -10). The functional consequences of 10 mutations have been investigated by expressing Ca V 2.1 channel subunits in heterologous systems (11-15). Because Ca V 2.1 channel expression is almost exclusively restricted to neuronal cells, 4 of these mutations have also been analyzed in neurons from Ca V 2.1 ␣ 1 Ϫ/Ϫ mice expressing hu...

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