@entity973 ( @entity974 , @entity974 ) is used clinically to improve neuromuscular function in @entity1 with @entity15 , @entity1566 , and @entity1737 . @entity974 can increase neuromuscular and synaptic transmission by directly stimulating high voltage-activated ( @entity3829 ) @entity141 channels independent of its blocking effect on voltage-activated K(+) channels. Here we provide new evidence that the potentiating effect of @entity974 on HVA @entity141 channels depends on the specific combination of voltage-activated @entity460 channel a1 (Cava1) and voltage-activated @entity460 channel b (Cavb) subunits. Among the four Cavb subunits examined, Cavb3 was the most significant subunit involved in the @entity974 -induced potentiation of both L-type and N-type currents. Of particular note, @entity974 at micromolar concentrations selectively potentiated L-type currents reconstituted with @entity18128 , a2  1, and Cavb3. In contrast, @entity974 potentiated N-type currents only at much higher concentrations and had little effect on P/Q-type currents. In a phrenic nerve-diaphragm preparation, blocking L-type @entity141 channels eliminated the potentiating effect of low concentrations of @entity974 on end-plate potentials. Furthermore, @entity974 enhanced the physical interaction of @entity18128 and @entity12357 subunits to Cavb3 and also increased their trafficking to the plasma membrane. Site-directed mutagenesis identified specific regions in the guanylate kinase, HOOK, and C-terminus domains of the Cavb3 subunit crucial to the ability of @entity974 to potentiate L-type and N-type currents. Our findings indicate that @entity974 potentiates HVA @entity141 channels by enhancing reciprocal @entity18128 -Cavb3 and @entity12357 -Cavb3 interactions. The therapeutic effect of @entity974 on neuromuscular function is probably mediated by its actions on Cavb3-containing L-type @entity141 channels.

Potentiation of high voltage-activated XXXX channels by @entity973 depends on subunit composition.

@entity1 :: ('9606', 'Species') :: ['patients'] @entity12357 :: ('774', 'Gene') :: ['Cav2.2'] @entity141 :: ('CHEBI:29108', 'Chemical') :: ['Ca(2+)'] @entity1737 :: ('MESH:D009157', 'Disease') :: ['myasthenia gravis'] @entity974 :: ('CHEBI:34385', 'Chemical') :: ['4-AP', 'fampridine'] @entity3829 :: ('CHEBI:545959', 'Chemical') :: ['HVA'] @entity1566 :: ('MESH:D013119', 'Disease') :: ['spinal cord injury'] @entity460 :: ('MESH:D002118', 'Chemical') :: ['calcium'] @entity973 :: ('MESH:D015761', 'Chemical') :: ['4-Aminopyridine'] @entity18128 :: ('775', 'Gene') :: ['Cav1.2'] @entity15 :: ('MESH:D009103', 'Disease') :: ['multiple sclerosis']
@entity460 :: (MESH:D002118,Chemical) :: ['calcium']
