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Thermodynamic regulation of NKCC1-mediated Cl- cotransport underlies plasticity of GABA(A) signaling in neonatal neurons.

Brumback AC, Staley KJ

Neuroscience Program, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.

In the adult brain, chloride (Cl-) influx through GABA(A) receptors is an important mechanism of synaptic inhibition. However, under a variety of circumstances, including acquired epilepsy, neuropathic pain, after trains of action potentials or trauma, and during normal early brain development, GABA(A) receptor activation excites neurons by gating Cl- efflux because the intracellular Cl- concentration (Cl(i)) is elevated. These findings require an inducible, active mechanism of chloride accumulation. We used gramicidin-perforated patch recordings to characterize Cl- transport via NKCC1, the principal neuronal Cl- accumulator, in neonatal CA1 pyramidal neurons. NKCC1 activity was required to maintain elevated Cl(i) such that GABA(A) receptor activation was depolarizing. Kinetic analysis of NKCC1 revealed reversible transmembrane Cl- transport characterized by a large maximum velocity (vmax) and high affinity (Km), so that NKCC1 transport was limited only by the net electrochemical driving force for Na+, K+, and Cl-. At the steady-state Cl(i), NKCC1 was at thermodynamic equilibrium, and there was no evidence of net Cl- transport. Trains of action potentials that have been previously shown to induce persistent changes in neuronal E(Cl) (reversal potential for Cl-) did not alter vmax or Km of NKCC1. Rather, action potentials shifted the thermodynamic set point, the steady-state Cl(i) at which there was no net NKCC1-mediated Cl- transport. The persistent increase in Cl(i) required intact alpha2/alpha3 Na+-K+-ATPase activity, indicating that trains of action potentials reset the thermodynamic equilibrium for NKCC1 transport by lowering Na(i). Activity-induced changes in Na+-K+-ATPase activity comprise a novel mechanism for persistent alterations in synaptic signaling mediated by GABA.

Published 7 February 2008 in J Neurosci, 28(6): 1301-12.
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