In alcohol-naïve systems, ethanol (<100 mM) exposure of calcium-gated BK channels perturbs physiology and behavior. Brief (several minutes) ethanol exposure usually leads to increased BK current, which results from ethanol interaction with a pocket mapped to the BK channel-forming slo1 protein cytosolic tail domain. The importance of this region in alcohol-induced intoxication has been addressed in Caenorhabditis elegans slo1 mutants. However, ethanol-induced BK activation is not universal as refractoriness and inhibition have been reported. The final effect depends on many factors, including intracellular calcium levels, slo1 isoform, BK beta subunit composition, post-translational modification of BK proteins, channel lipid microenvironment and type of ethanol administration. Studies in Drosophila melanogaster, Caenorhabditis elegans and rodents show that protracted/repeated ethanol administration leads to tolerance to alcohol-induced modification of BK-driven physiology and behavior. Unveiling the mechanisms underlying tolerance is of major importance, as tolerance to alcohol has been proposed as predictor of risk for alcoholism.

Carlin KP, Liu J, Jordan LM. Postnatal changes in the inactivation properties of voltage-gated sodium channels contribute to the mature firing pattern of spinal motoneurons. J Neurophysiol 99: 2864 -2876, 2008. First published April 9, 2008 doi:10.1152/jn.00059.2008. Most mammals are born with the necessary spinal circuitry to produce a locomotor-like pattern of neural activity. However, rodents seldom demonstrate weight-supported locomotor behavior until the second or third postnatal week, possibly due to the inability of the neuromuscular system to produce sufficient force during this early postnatal period. As spinal motoneurons mature they are seen to fire an increasing number of action potentials at an increasing rate, which is a necessary component of greater force production. The mechanisms responsible for this enhanced ability of motoneurons are not completely defined. In the present study we assessed the biophysical properties of the developing voltage-gated sodium current to determine their role in the maturing firing pattern. Using dissociated postnatal lumbar motoneurons in short-term culture (18 -24 h) we demonstrate that currents recorded from the most mature postnatal age group (P10 -P12) were significantly better able to maintain channels in an available state during repetitive stimulation than were the younger age groups (P1-P3, P4 -P6, P7-P9). This ability correlated with the ability of channels to recover more quickly and more completely from an inactivated state. These age-related differences were seen in the absence of changes in the voltage dependence of channel gating. Differences in both closed-state inactivation and slow inactivation were also noted between the age groups. The results indicate that changes in the inactivation properties of voltage-gated sodium channels are important for the development of a mature firing pattern in spinal motoneurons.