Phospholipids and the origin of cationic gating charges in voltage sensors

Abstract

Cells communicate with their external environment through physical and chemical processes that take place in the cell-surrounding membrane. The membrane serves as a barrier as well as a special environment in which membrane proteins are able to carry out important processes. Certain membrane proteins have the ability to detect the membrane voltage and regulate ion conduction or enzyme activity. Such voltage-dependent processes rely on the action of protein domains known as voltage sensors, which are embedded inside the cell membrane and contain an excess of positively charged amino acids, which react to an electric field. How does the membrane create an environment suitable for voltage sensors? Here we show under a variety of conditions that the function of a voltage-dependent K+ channel is dependent on the negatively charged phosphodiester of phospholipid molecules. A non-voltage-dependent K+ channel does not exhibit the same dependence. The data lead us to propose that the phospholipid membrane, by providing stabilizing interactions between positively charged voltage-sensor arginine residues and negatively charged lipid phosphodiester groups, provides an appropriate environment for the energetic stability and operation of the voltage-sensing machinery. We suggest that the usage of arginine residues in voltage sensors is an adaptation to the phospholipid composition of cell membranes.

7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome

“…It seems that VSDs and not the pore domain of Kv channels require the lipid belt [50]. Recent structure function studies show that the VSDs of Kv1.2 are positioned at the corners of the square-shaped PD creating deep grooves between the adjacent subunits.…”

Tetraphenylporphyrin derivative specifically blocks members of the voltage-gated potassium channel subfamily Kv1

“…29 Negatively charged phospholipid head groups may serve as counter charges for the positively charged amino acid side chains of the voltage sensor. 30 Hence, binding of the positively charged por3 to phospholipid head groups potentially affects this interaction and thus affects voltage-dependence of Kv channels. Alternatively, negatively charged amphiphiles, for example, free polyunsaturated fatty acids (PUFAs) can potentially bind to the voltage sensor, modulating the voltage-dependence of Kv channel activation.…”

Functional diversity of potassium channel voltage-sensing domains

“…These charge-charge interactions are necessary to reduce the energy of charged residues in a low dielectric constant environment such as the lipid bilayer. Apart from the intra protein salt bridges, positive charges are stabilized by interactions with phospholipid head groups 68,69 and hydration waters present in the inner and outer vestibules. 28 It is worth mentioning that other voltage-gated potassium channels such as the cardiac potassium channel hERG, the sperm SpIH inward rectifier, a member of the HCN type of channels and the Slo maxi-K channels, seem to share the same mechanism of activation of the VSD domain described above, [70][71][72] possibly implying that the VSDs from these channels preserve the canonical structure described previously for Kv channels.…”