PREGABALIN MODULATION OF NEUROTRANSMITTER RELEASE IS MEDIATED BY CHANGING CAV2.1 CALCIUM CHANNELS ACTIVATION/INACTIVATION PROPERTIES.

DI GUILMI MN ; URBANO FJ; GONZALEZ-INCHAUSPE C; UCHITEL OD

San Francisco, CA, USA

Congreso; Biophysical Society 54th annual meeting; 2010

Biophysical Society 54th annual meeting

Mechanisms by which Pregabalin (PGB) might act as an anticonvulsant are unknown. The á2-ä 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 ìM. 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 minisfrequencies -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 pulseprotocol.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).