Molecular structure of an open human KATP channel

KATP channels are metabolic sensors that translate intracellular ATP/ADP balance into membrane excitability. The molecular composition of KATP includes an inward-rectifier potassium channel (Kir) and an ABC transporter–like sulfonylurea receptor (SUR). Although structures of KATP have been determined in many conformations, in all cases, the pore in Kir is closed. Here, we describe human pancreatic KATP (hKATP) structures with an open pore at 3.1- to 4.0-Å resolution using single-particle cryo-electron microscopy (cryo-EM). Pore opening is associated with coordinated structural changes within the ATP-binding site and the channel gate in Kir. Conformational changes in SUR are also observed, resulting in an area reduction of contact surfaces between SUR and Kir. We also observe that pancreatic hKATP exhibits the unique (among inward-rectifier channels) property of PIP2-independent opening, which appears to be correlated with a docked cytoplasmic domain in the absence of PIP2.

Diversity in the Structure and Function of Ion Channels

Voltage clamp and patch clamp techniques are used to reveal heterogeneity of ion currents carried through voltage-dependent sodium, calcium, and potassium channels. Advances in channel molecular biology have made it clear that the diversity of ion channels is even greater than was suspected from these electrophysiological measurements. This diversity is achieved by several different mechanisms, including the existence of multiple genes for the pore-forming α‎ subunits of ion channels, alternative splicing of the messenger RNA transcribed from each individual gene, formation of heterotetramers containing different α‎ subunits of potassium channels, and modulation of channel properties by auxiliary subunits that may themselves comprise a large and diverse family of proteins. Moreover, potassium channels can be further categorized into voltage-dependent, calcium-dependent, sodium-dependent, two-pore, and inward rectifier channels. Emerging evidence suggests that many human diseases are associated with dysfunction of individual classes of ion channels in neurons.

Potassium currents in human myogenic cells from healthy and congenital myotonic dystrophy foetuses

The whole-cell patch clamp technique was used to record potassium currents in in vitro differentiating myoblasts isolated from healthy and myotonic dystrophy type 1 (DM1) foetuses carrying 2000 CTG repeats. The fusion of the DM1 myoblasts was reduced in comparison to that of the control cells. The dystrophic muscle cells expressed less voltage-activated K+ (delayed rectifier and non-inactivating delayed rectifier) and inward rectifier channels than the age-matched control cells. However, the resting membrane potential was not significantly different between the control and the DM1 cells. After four days in a differentiation medium, the dystrophic cells expressed the fast-inactivating transient outward K+ channels, which were not observed in healthy cells. We suggest that the low level of potassium currents measured in differentiated DM1 cells could be related to their impaired fusion.