Abstract
As their name implies, cation channels allow the regulated flow of cations such as sodium, potassium, calcium, and magnesium across cellular and intracellular membranes. Cation channels have long been known for their fundamental roles in controlling membrane potential and excitability in neurons and muscle. In this review, we provide an update on the recent advances in our understanding of the structure–function relationship and the physiological and pathophysiological role of cation channels. The most exciting developments in the last two years, in our opinion, have been the insights that cryoelectron microscopy has provided into the inner life and the gating of not only voltage-gated channels but also mechanosensitive and calcium- or sodium-activated channels. The mechanosensitive Piezo channels especially have delighted the field not only with a fascinating new type of structure but with important roles in blood pressure regulation and lung function.
Highlights
Cation channels mediate the flow of cations (Na+, K+, Ca2+, and Mg2+) across hydrophobic lipid membrane barriers, allowing both excitable cells such as neurons or muscle and non-excitable cells such as lymphocytes and endothelial cells to regulate membrane potential, Ca2+ signaling, and various other cellular processes[1]
We provide an update on what, in our opinion, constitutes the most exciting new findings concerning cation channels during the last two years, namely our increased understanding of gating mechanisms of more unusual, non-voltage-gated channels such as Slack (KNa1.1), KCa3.1 (SK4), ENaC, TCP1, or Piezo[1]
The structure, which was solved at 3.5-Å resolution in the presence and absence of cyclic adenosine monophosphate (cAMP), explains the 4:1 potassium-to-sodium permeability ratio of hyperpolarization-activated cyclic nucleotide-gated (HCN) and shows an unusually long S4 helix that extends in the cytoplasm to stabilize a closed pore in the presence of a depolarized voltage sensor
Summary
Cation channels mediate the flow of cations (Na+, K+, Ca2+, and Mg2+) across hydrophobic lipid membrane barriers, allowing both excitable cells such as neurons or muscle and non-excitable cells such as lymphocytes and endothelial cells to regulate membrane potential, Ca2+ signaling, and various other cellular processes[1]. Together with the previously solved closed Slack structure[12], the Hite and MacKinnon article, which collected images at five different Na+ concentrations, shows that Slack exists in multiple closed conformations from which an open conformation emerges in a highly Na+-dependent manner[12], suggesting that opening of this ligand-gated channel is a highly concerted, switch-like process In another effort from the MacKinnon laboratory, the structure of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel member 1 was elucidated[11]. The structure, which was solved at 3.5-Å resolution in the presence and absence of cAMP, explains the 4:1 potassium-to-sodium permeability ratio of HCN and shows an unusually long S4 helix that extends in the cytoplasm to stabilize a closed pore in the presence of a depolarized voltage sensor These structural features suggest a gating mechanism in which downward displacement of the S4 helix during membrane hyperpolarization disrupts these stabilizing interactions to open the channel, explaining HCN’s reversed polarity of voltage dependence. They are a diverse group of cation channels that are often relatively non-selective and
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