The P/Q-type voltage-dependent calcium channel as pharmacological target in spinocerebellar ataxia type 6: gabapentin and pregabalin may be of therapeutic benefit.
Voltage-dependent calcium channels (VDCCs) are heteromultimeric complexes that mediate calcium influx into cells in response to changes in membrane potential. The alpha1A subunit, encoded by the CACNA1A gene, is the pore-forming subunit specific to the neuronal P/Q-type VDCCs. These are implicated in fast excitatory and inhibitory neurotransmission. Their highest levels of expression are found in the Purkinje cell layer of the cerebellum, and in the hippocampus. Spinocerebellar ataxia type 6 (SCA 6) is an autosomal dominant cerebellar degeneration that shares neuropathological findings with late-onset cortical cerebellar atrophy (CCA). It is caused by an abnormal expansion of a trinucleotide (CAG) repeat in exon 47 of CACNA1A, on chromosome 19p13. This translates into a polyglutamine (polyQ) tract of prolonged length in the carboxyl terminal of the alpha1A subunit. Heterologous expression of mutated alpha1A subunits results in increased channel inactivation in electrophysiological tests. No treatment is known to improve SCA 6 at present, as none of the available drugs is able to reverse alpha1A dysregulation, nor disturbed protein aggregation, transport and localization in this disease. The drugs gabapentin and pregabalin interact with the alpha2delta subunit of the P/Q-type VDCCs. Gabapentin and pregabalin slow the rate of inactivation in recombinant P/Q-type VDCCs, expressed in Xenopus oocytes. These drugs improve ataxia in cases of CCA, olivopontocerebellar atrophy and ataxia-telangiectasia. On the basis of the neuropathological identity of SCA 6 with CCA, and given the capacity of gabapentin and pregabalin to decrease P/Q-type VDCCs inactivation, in this paper the authors put forward the hypothesis that the administration of gabapentin and pregabalin might prove beneficial in SCA 6 as the ataxia caused by this disease would be expected to improve. The authors hope that researchers working with this illness will be inspired and encouraged to undertake the appropriate clinical and experimental work.
Gazulla
José
J
Department of Neurology, "Miguel Servet" University Hospital, Zaragoza, Spain.
Tintoré
Mari A
MA
D000588:Amines / Q000008:administration & dosage*; D002121:Calcium Channel Blockers / Q000008:administration & dosage*; D020865:Calcium Channels, P-Type / Q000187:drug effects* / Q000378:metabolism; D020907:Calcium Channels, Q-Type / Q000187:drug effects* / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods; D000077206:Gabapentin; D006801:Humans; D000069583:Pregabalin; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000188:drug therapy* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*
D000588:Amines; D002121:Calcium Channel Blockers; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D003509:Cyclohexanecarboxylic Acids; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin