Pregabalin action at a model synapse: binding to presynaptic calcium channel alpha2-delta subunit reduces neurotransmission in mice.
Pregabalin, ((S)-3-(aminomethyl)-5-methylhexanoic acid, also known as (S)-3-isobutyl GABA, Lyricatrade mark) is approved for treatment of certain types of peripheral neuropathic pain and as an adjunctive therapy for partial seizures of epilepsy both the EU and the USA and also for generalized anxiety disorder in the EU. Though pregabalin binds selectively to the alpha(2)-delta (alpha(2)-delta) auxiliary subunit of voltage-gated calcium channels, the cellular details of pregabalin action are unclear. The high density of alpha(2)-delta in skeletal muscle fibers raises the question of whether pregabalin alters excitation-contraction coupling. We used the mouse soleus neuromuscular junction from mice containing an artificially mutated alpha(2)-delta Type 1 protein (R217A) as a model to examine the effect of pregabalin. Pregabalin reduced nerve-evoked muscle contractions by 16% at a clinically relevant concentration of 10 muM in wildtype mice. When acetylcholine receptors were blocked with curare, pregabalin had no effect on contraction from direct stimulation of muscle, suggesting a lack of drug effects on contraction coupling. Our data are consistent with pregabalin having no effect on striated muscle L-type calcium channel function. However, in mice expressing mutant (R217A) alpha(2)-delta Type 1, there was no significant effect of pregabalin on nerve-evoked muscle contraction. We propose that pregabalin reduces presynaptic neurotransmitter release without altering postsynaptic receptors or contraction coupling and that these effects require high affinity binding to alpha(2)-delta Type 1 auxiliary subunit of presynaptic voltage-gated calcium channels.
Joshi
Indu
I
Department CNS Biology, Pfizer Global R&D, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
Taylor
Charles P
CP
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects; D009154:Mutation / Q000502:physiology; D009469:Neuromuscular Junction / Q000187:drug effects; D000069583:Pregabalin; D017661:Receptors, Presynaptic / Q000187:drug effects*; D013045:Species Specificity; D013569:Synapses / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
D000927:Anticonvulsants; C512066:CACNA2D1 protein, mouse; D015220:Calcium Channels; D017661:Receptors, Presynaptic; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid