Work over the past three decades has greatly advanced our understanding of the regulation of Kir K+ channels by polyanionic lipids of the phosphoinositide (e.g., PIP2) and fatty acid metabolism (e.
View Article and Find Full Text PDFOtopetrins comprise a family of proton-selective channels that are critically important for the mineralization of otoliths and statoconia in vertebrates but whose underlying cellular mechanisms remain largely unknown. Here, we demonstrate that otopetrins are critically involved in the calcification process by providing an exit route for protons liberated by the formation of CaCO Using the sea urchin larva, we examined the otopetrin ortholog , which is exclusively expressed in the calcifying primary mesenchymal cells (PMCs) that generate the calcitic larval skeleton. expression is stimulated during skeletogenesis, and knockdown of impairs spicule formation.
View Article and Find Full Text PDFPotassium (K) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K channels gated at their selectivity filter (SF), including many two-pore domain K (K) channels, voltage-gated hERG (human ether-à-go-go-related gene) channels and calcium (Ca)-activated big-conductance potassium (BK)-type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K occupancy, and open the filter gate.
View Article and Find Full Text PDFTwo-pore domain (K2P) K(+) channels are major regulators of excitability that endow cells with an outwardly rectifying background "leak" conductance. In some K2P channels, strong voltage-dependent activation has been observed, but the mechanism remains unresolved because they lack a canonical voltage-sensing domain. Here, we show voltage-dependent gating is common to most K2P channels and that this voltage sensitivity originates from the movement of three to four ions into the high electric field of an inactive selectivity filter.
View Article and Find Full Text PDF