Intrinsic activationinactivation parameters of CaV2.1 calcium channels are shifted by Pregabalin, modulating neurotransmitter release

DI GUILMI, MN; URBANO, FJ; GONZALEZ INCHAUSPE, C ; UCHITEL, OD.

Conferencia; Second International Calcium Channel Conference; 2010

Mechanisms by which Pregabalin (PGB) might act as an anticonvulsant are unknown. The α2-δ type 1 auxiliary subunit of voltage-gated calcium channels is the primary high-affinity binding site for PGB. Here we studied PGB effects on excitatory transmitter release of principal neurons of mice Medial Nucleus of the Trapezoid Body as well as we recorded presynaptic calcium currents (IpCa) present on the afferent called Calyx of Held in brainstem slices using whole cell patch clamp recordings. We found that a dose-response relationship showed a maximum drug effect at 500 μM. At this concentration, PGB reduced the amplitude of EPSCs by a 30%. No differences were observed in the depression rate from high frequency trains but a faster rate of recovery from synaptic depression at 100 Hz was observed in the presence of PGB (p=0.043). We found no differences in the mean amplitude of miniature EPSCs while observing greater minis frequencies -PGB versus +PGB conditions (1.71±0.35 Hz and 0.49±0.06 Hz, respectively (p=0.0044)). On the other hand, multiple effects on IpCa by PGB were observed. PGB blocked CaV2.1 channels-mediated currents and decrease their facilitation during 100Hz train, without changing their voltage-sensitive activation. However, two pulses inactivation protocol showed a larger rescue of the inactivation. Additionally, the inactivation curve observed with PGB showed a clear change on the kinetic but not on the half-activation voltage using a long conditioning pulse protocol. The results presented in this work could help to elucidate the possible PGB actions on cortical areas and its potential pharmacological action on neuropathotogies. Supported by: UBACYT X-223; FONCYT (ANPCyT) PICT 2005-32113; 2006-199, Wellcome Trust (to ODU); FONCYT (ANPCyT) PICT 2007-01009, PIDRI-PRH 2007 (to FU) Commercial Relationship: M.N. Di Guilmi, None; F.J. Urbano, None; C. Gonzalez-