No abstract

The S4 transmembrane segment is the primary voltage sensor in voltage-dependent ion channels. Its movement in response to changes in membrane potential leads to the opening of the activation gate, which is formed by a separate structural component, the S6 segment. Here we show in voltage-, Ca 2؉ -, and Mg 2؉ -dependent, large conductance K ؉ channels that the S4 segment participates not only in voltage-but also Mg 2؉ -dependent activation. Mutations in S4 and the S4-S5 linker alter voltagedependent activation and have little or no effect on activation by micromolar Ca 2؉ . However, a subset of these mutations in the C-terminal half of S4 and in the S4-S5 linker either reduce or abolish the Mg 2؉ sensitivity of channel gating. Cysteine residues substituted into positions R210 and R213, marking the boundary between S4 mutations that alter Mg 2؉ sensitivity and those that do not, are accessible to a modifying reagent [sodium (2-sulfonatoethyl)methane-thiosulfonate] (MTSES) from the extracellular and intracellular side of the membrane, respectively, at ؊80 mV. This implies that interactions between S4 and a cytoplasmic domain may be involved in Mg 2؉ -dependent activation. These results indicate that the voltage sensor is critical for Mg 2؉ -dependent activation and the coupling between the voltage sensor and channel gate is a converging point for voltage-and Mg 2؉ -dependent activation pathways.

Sieling FH, Canavier CC, Prinz AA. Predictions of phaselocking in excitatory hybrid networks: excitation does not promote phase-locking in pattern-generating networks as reliably as inhibition.

These data establish direct causality for the contributions of distinct synaptic and nonsynaptic adaptive processes to complementary facets of a compulsive behavior resulting from operant reward learning.