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Cover Image
Cover Image
Cover picture: Ramachandran plot, a plot of the torsional angles—phi (φ) and psi (ψ)—of the residues contained in a protein, was used to evaluate the reliability of simulated TRPM2 NUDT9-H structure by homology modeling, which provided supporting evidence for Yu’s work in identification of ADPR binding sites in the TRPM2 channel (see Research Article by Yu et al., 219–235).
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Editorial
The state of the community: JGP in 2017
Amid a difficult year for science and scientists, The Journal of General Physiology is thriving and gearing up for its 100th anniversary celebrations.
Research News
A missense mutation makes a mess of Ca2+ sensing
A new JGP study shows how a disease-causing mutation in RyR2 dramatically alters channel behavior.
Commentary
It’s not funny: How changes in If limit maximum heart rate with aging
Robertson highlights recent work showing how aging limits pacemaking by the funny current, If, in the sinoatrial node.
Review
Extraoral bitter taste receptors in health and disease
Article
Extensive Ca2+ leak through K4750Q cardiac ryanodine receptors caused by cytosolic and luminal Ca2+ hypersensitivity
The K4750Q mutation in ryanodine receptor 2 causes severe catecholaminergic polymorphic ventricular tachycardia. Uehara et al. reveal extensive Ca2+ leak through this mutant receptor and show it is caused by altered gating kinetics, increased Ca2+ sensitivity, and the absence of Ca2+-dependent inactivation.
Identification of the ADPR binding pocket in the NUDT9 homology domain of TRPM2
ADP ribose (ADPR) is an endogenous ligand for the transient receptor potential melastatin 2 (TRPM2) channel. Yu et al. identify 11 residues in the NUDT9 homology domain of TRPM2 that form a binding site for ADPR involving van der Waals, polar solvation, and electronic interactions.
Cyclic AMP reverses the effects of aging on pacemaker activity and If in sinoatrial node myocytes
Aging reduces pacemaker activity and shifts the voltage dependence of activation of the funny current, If, in sinoatrial node myocytes. Sharpe et al. find that these effects of aging can be reversed by application of exogenous cAMP but not by stimulation of endogenous cAMP.
The intrinsically liganded cyclic nucleotide–binding homology domain promotes KCNH channel activation
hEAG1 is a member of the KCNH family of ion channels, which are characterized by C-terminal regions with homology to cyclic nucleotide–binding domains (CNBhDs). Zhao et al. show that an “intrinsic ligand” occupying the CNBhD binding pocket promotes the activated and open state of the channel.
The HOOK region of voltage-gated Ca2+ channel β subunits senses and transmits PIP2 signals to the gate
Voltage-gated Ca2+ channels contain β subunits that regulate channel gating. Park et al. conduct a comprehensive analysis of the role of the β subunit HOOK region and show that its B domain is important for PIP2 regulation of channel gating and that its A domain modulates this effect.
Calmodulin limits pathogenic Na+ channel persistent current
The molecular mechanisms controlling “persistent” current through voltage-gated Na+ channels are poorly understood. Yan et al. show that apocalmodulin binding to the intracellular C-terminal domain limits persistent Na+ flux and accelerates inactivation across the voltage-gated Na+ channel family.
