Voltage-gated channels open paths for ion permeation upon changes in membrane potential, but how voltage changes are coupled to gating is not entirely understood. Two modules can be recognized in voltage-gated potassium channels, one responsible for voltage sensing (transmembrane segments S1 to S4), the other for permeation (S5 and S6). It is generally assumed that the conversion of a conformational change in the voltage sensor into channel gating occurs through the intracellular S4–S5 linker that provides physical continuity between the two regions. Using the pathophysiologically relevant KCNH family, we show that truncated proteins interrupted at, or lacking the S4–S5 linker produce voltage-gated channels in a heterologous model that recapitulate both the voltage-sensing and permeation properties of the complete protein. These observations indicate that voltage sensing by the S4 segment is transduced to the channel gate in the absence of physical continuity between the modules.

The basic architecture of the voltage-dependent K⁺ channels (Kv channels) corresponds to a transmembrane protein core in which the permeation pore, the voltage-sensing components and the gating machinery (cytoplasmic facing gate and sensor–gate coupler) reside. Usually, large protein tails are attached to this core, hanging toward the inside of the cell. These cytoplasmic regions are essential for normal channel function and, due to their accessibility to the cytoplasmic environment, constitute obvious targets for cell-physiological control of channel behavior. Here we review the present knowledge about the molecular organization of these intracellular channel regions and their role in both setting and controlling Kv voltage-dependent gating properties. This includes the influence that they exert on Kv rapid/N-type inactivation and on activation/deactivation gating of Shaker-like and eag-type Kv channels. Some illustrative examples about the relevance of these cytoplasmic domains determining the possibilities for modulation of Kv channel gating by cellular components are also considered.

The electrochemical gradient of protons (ΔμΔH⁺) across the plasma membrane of Saccharomyces× 17/17 has been measured as a function of external pH and the external potassium concentration. The proton gradient (ΔpH) has been determined from the distribution of the weak permeable [¹⁴C]propionic acid across the plasma membrane. The accumulation of the lipophilic cation [³H]tetraphenylphosphonium has been used to calculate the membrane potential (ΔΨ). It has been observed that yeast cells are able to maintain a ΔμH⁺ whose values vary from −150 mV at pH 4.5 to −90 mV at pH 7.0. When considered independently ΔpH and ΔΨ have values which vary reciprocally depending on the external pH. At pH 4.5 δpH is the main component of ΔμH⁺ having a value of −105 mV. Then its value decreases as the external pH increases reaching a value of −10 mV at pH 7.0. At this pH ΔΨ is the main cornponcnt of δμ,H+⁺ having a value of −80 mV, while at pH 4.5 its value is −45 mV. As the external concentration of potassium increases the value of ΔΨ becomes smaller. This decrease in ΔΨ is accompanied by an increase in the value of ΔpH. For any given concentration of potassium, the decrease in ΔΨ is larger than the increase in δpH the net result being, therefore, a decrease in the protonmotive force. In cells treated with the protonophores carbonylcyanide M‐chlorophenylhydrazone or dinitrophenol, δpH is drastically reduced at every pH while ΔΨ is not significantly changed. Upon treatment with dicyclohexylcarbodiimide ΔpH is reduced at any pH tested. This decrease is accompanied by an increase in the value of ΔΨ so that the total protonmotive force remains essentially constant. If the treatment with dicyclohexylcarbodiiniide is carried out in the presence of 200 mM potassium carbodiimide effect on ΔpH and ΔΨ is abolished. The results show that the movements of H⁺ and K⁺ are closely connected and play a central role in the establishment and maintenance of an energized state of the cell. They further suggest that δμH⁺ regulates the fluxes of protons while ΔμH⁺ regulates the establishment of a ΔμK⁺.