PIEZO2-dependent rapid pain system in humans and mice.

The PIEZO2 ion channel is critical for transducing light touch into neural signals but is not considered necessary for transducing acute pain in humans. Here, we discovered an exception - a form of mechanical pain evoked by hair pulling. Based on observations in a rare group of individuals with PIEZO2 deficiency syndrome, we demonstrated that hair-pull pain is dependent on PIEZO2 transduction.

Mutations at the M2 and M3 Transmembrane Helices of the GABARs α and β Subunits Affect Primarily Late Gating Transitions Including Opening/Closing and Desensitization.

GABA type A receptors (GABARs) belong to the pentameric ligand-gated ion channel (pLGIC) family and play a crucial role in mediating inhibition in the adult mammalian brain. Recently, a major progress in determining the static structure of GABARs was achieved, although precise molecular scenarios underlying conformational transitions remain unclear. The ligand binding sites (LBSs) are located at the extracellular domain (ECD), very distant from the receptor gate at the channel pore.

Interaction between GABA receptor α and β subunits at the N-terminal peripheral regions is crucial for receptor binding and gating.

Pentameric ligand gated ion channels (pLGICs) are crucial in electrochemical signaling but exact molecular mechanisms of their activation remain elusive. So far, major effort focused on the top-down molecular pathway between the ligand binding site and the channel gate. However, recent studies revealed that pLGIC activation is associated with coordinated subunit twisting in the membrane plane.

The C loop at the orthosteric binding site is critically involved in GABA receptor gating.

GABA receptors (GABARs) play a crucial role in mammalian adult brain inhibition. The dysfunction of GABAergic drive is related to such disorders as epilepsy, schizophrenia, and depression. Substantial progress has recently been made in describing the static structure of GABARs, but the molecular mechanisms that underlie the activation process remain elusive.

Distinct Modulation of Spontaneous and GABA-Evoked Gating by Flurazepam Shapes Cross-Talk Between Agonist-Free and Liganded GABA Receptor Activity.

GABA receptors (GABARs) play a crucial inhibitory role in the CNS. Benzodiazepines (BDZs) are positive modulators of specific subtypes of GABARs, but the underlying mechanism remains obscure. Early studies demonstrated the major impact of BDZs on binding and more recent investigations indicated gating, but it is unclear which transitions are affected.