Table of Contents
Brelidze examines recent data revealing the new role of the intrinsic ligand in hERG potassium channel gating.
Tembo and Carlson reflect on recent work describing a new role for Ano1 in lymphatic collecting vessels.
Milestones in Physiology
Kay and Blaustein recount the history of the pump-leak mechanism, which stabilizes cell volume by pumping sodium ions out of cells.
Anantharam and Kreutzberger describe the reductionist approaches that have begun to unveil the mechanistic basis of secretion.
Kainate receptors are involved in several neuropathologies, but their gating process remains to be fully understood. Wilding and Huettner identify two residues at the extracellular end of the GluK2 inner helix where cysteine substitution results in direct activation by cadmium.
The structural changes that underlie ligand activation of nicotinic acetylcholine receptors remain unclear. Using computational tools, Tripathy et al. show that the distance between a nitrogen in the agonist and the center of the neurotransmitter binding pocket provides a good estimate of agonist affinity, efficacy, and efficiency.
Receptors convert agonist-binding energy into conformational change. Nayak et al. describe a new agonist trait, efficiency, as the fraction of binding energy transformed into the mechanical work of conformational change and suggest that it is a general attribute of agonist action at receptor-binding sites.
The hERG potassium channel intrinsic ligand regulates N- and C-terminal interactions and channel closure
An intersubunit interaction between the N-terminal PAS domain and C-terminal cyclic nucleotide binding homology domain (CNBHD) regulates slow deactivation in hERG potassium channels. By mutating the intrinsic ligand, Codding and Trudeau disrupt slow deactivation and prevent the PAS-CNBHD interaction.
Helix–strand interaction regulates stability and aggregation of the human mitochondrial membrane protein channel VDAC3
Human mitochondrial VDACs bind amyloidogenic proteins, but do not intrinsically aggregate. Gupta and Mahalakshmi find that an interaction between the N-terminal α-helix and strands β7–β9 regulates VDAC aggregation and stability, providing a plausible mechanism for VDAC coaggregation in cells.
Proteins of the L-type amino acid transporter (LAT) subfamily take up amino acids from the environment for use in the cell. Bartoccioni et al. show that the bacterial amino acid exchanger BasC is functionally similar to the human LAT Asc1, making BasC a useful model for this class of transporters.
Comparison of ion transport determinants between a TMEM16 chloride channel and phospholipid scramblase
The I-V relation of the TMEM16A channel is linear, whereas that of the TMEM16F scramblase is outwardly rectifying. Nguyen et al. show that rectification of TMEM16A is regulated by the charge of residue 584 but that rectification of TMEM16F is affected by aromatic residues at the equivalent position.
Ano1 mediates pressure-sensitive contraction frequency changes in mouse lymphatic collecting vessels
Lymphatic vessels display pressure-dependent contractions whose frequency is modulated by ion channel activity in lymphatic muscle. Zawieja et al. show that the Ca2+-activated Cl− channel Anoctamin 1 sets the lymphatic contraction rate by providing depolarizing current between action potentials.
Recovery from acidosis is a robust trigger for loss of force in murine hypokalemic periodic paralysis
Hypokalemic periodic paralysis causes episodes of muscle weakness. Mi et al. investigate the rest-induced weakness that occurs after vigorous exercise and find that acidosis, as occurs with exercise, leads to accumulation of myoplasmic Cl−, which favors a depolarized resting potential when pH returns to normal.
SR Ca2+ leak in skeletal muscle fibers acts as an intracellular signal to increase fatigue resistance
Skeletal muscle oxidative capacity and fatigue resistance can be improved with endurance training, but the mechanism is not fully understood. Ivarsson et al. find that the signaling pathway that increases fatigue resistance in muscle is triggered by a mild Ca2+ leak from the sarcoplasmic reticulum.
Comparing models with one versus multiple myosin-binding sites per actin target zone: The power of simplicity
Models of muscle contraction often assume that a myosin motor interacts with areas of one to three distinct binding sites along an actin filament. Månsson shows that computational models employing different numbers of sites return similar predictions, suggesting one-site models are often sufficient.
Ryanodine receptors in the sarcoplasmic reticulum and voltage-gated Ca2+ channels on T tubules or the cell membrane coassemble into structures called couplons. Ríos et al. use quantitative simulations to test a simple hypothesis on the organization of couplons and derive functional implications of this arrangement.