Journal of General Physiology

Journal of General Physiology The Journal of General Physiology publishes research in physiological problems at cellular and molecular level. Published by Rockefeller University Press.
The Journal of General Physiology publishes peer-reviewed research in physiological problems at the cellular and molecular level. Est. 1918, published by The Rockefeller University Press.

The Journal of General Physiology publishes peer-reviewed research in biological, chemical, or physical mechanisms of broad physiological significance, with an emphasis on physiological problems at the cellular and molecular level. Areas include, but are not limited to: - Membrane protein physiology - Protein structure and dynamics - Lipid and membrane biophysics - Cell mechanics - Intracellular and intercellular signaling All editorial decisions are made by research-active scientists in conjunction with in-house scientific editors. JGP provides free online access to many article types from the date of publication and to all archival content. Established in 1918, JGP is published by The Rockefeller University Press. For more information, visit http://jgp.rupress.org. Follow us on Twitter: https://twitter.com/JGenPhysiol

Mission: The mission of JGP is to publish articles that elucidate basic biological, chemical, or physical mechanisms of broad physiological importance. GENERAL PHYSIOLOGY is the study of biological mechanisms through analytical investigations, which decipher the molecular and cellular mechanisms underlying biological function at all levels of organization.

High-resolution structural information is invaluable for understanding muscle function. Savich et al. (https://bit.ly/2R...
06/26/2019
Myosin lever arm orientation in muscle determined with high angular resolution using bifunctional spin labels

High-resolution structural information is invaluable for understanding muscle function. Savich et al. (https://bit.ly/2RxjOet) use bifunctional spin labeling to determine the orientation of the myosin lever arm in muscle fibers at high resolution under ambient conditions, augmenting previous insights obtained from fluorescence and EM.

Despite advances in x-ray crystallography, cryo-electron microscopy (cryo-EM), and fluorescence polarization, none of these techniques provide high-resolution structural information about the myosin light chain domain (LCD; lever arm) under ambient cond...

We are pleased to present a collection of articles on mechanisms of membrane transport, which have been curated from rec...
06/25/2019
Mechanisms of Membrane Transport

We are pleased to present a collection of articles on mechanisms of membrane transport, which have been curated from recent issues of JGP.

The articles in this collection highlight some of the recent advances in this field and demonstrate the range of tools and techniques – both experimental and computational – that are being deployed to integrate structure and dynamics with function.

We are pleased to present a collection of articles (https://bit.ly/2Rs9STG) on the structure, function and pharmacology ...
06/24/2019
Structure, function, and pharmacology of ion channels

We are pleased to present a collection of articles (https://bit.ly/2Rs9STG) on the structure, function and pharmacology of ion channels, which have been curated from recent issues of JGP.

Ion channels are transmembrane proteins that are critical components of both excitable and non-excitable cells. Without ion channels, neurons would not be able to communicate with other cells, muscle would not be able to contract and our immune system would not be able to fight infection. Indeed, wh...

Heart rate is set by the specialized tissue of the sinoatrial node. Lin et al. (https://bit.ly/2XszGEt) demonstrate a no...
06/21/2019
Regulation of heart rate and the pacemaker current by phosphoinositide 3-kinase signaling

Heart rate is set by the specialized tissue of the sinoatrial node. Lin et al. (https://bit.ly/2XszGEt) demonstrate a novel role for phosphoinositide 3-kinase in regulating cardiac pacemaking currents independently of the autonomic nervous system, a finding with relevance for diabetes, heart disease, and cancer.

Heart rate in physiological conditions is set by the sinoatrial node (SN), the primary cardiac pacing tissue. Phosphoinositide 3-kinase (PI3K) signaling is a major regulatory pathway in all normal cells, and its dysregulation is prominent in diabetes, c...

Andrew Harris (https://bit.ly/2ETx8oz) explored the development of our current understanding of electrical coupling betw...
06/20/2019
Electrical coupling and its channels

Andrew Harris (https://bit.ly/2ETx8oz) explored the development of our current understanding of electrical coupling between cells and the channels that mediate it, highlighting the contributions of the Journal of General Physiology. #ThrowbackThursday

As the physiology of synapses began to be explored in the 1950s, it became clear that electrical communication between neurons could not always be explained by chemical transmission. Instead, careful studies pointed to a direct intercellular pathway of ...

Immunohistochemical analysis and subcellular localization of Cav1.1 and Cav1.2 (the skeletal and cardiac isoform of the ...
06/19/2019

Immunohistochemical analysis and subcellular localization of Cav1.1 and Cav1.2 (the skeletal and cardiac isoform of the α 1 subunit of the DHPR, respectively) in single muscle fibers from WT (top) and ryr3−/− (middle) mice. The image shows mouse anti-Cav1.1 (red), rabbit anti-Cav1.2 (green), and myonuclei (DAPI, blue). The bottom panel shows staining of mouse EDL fibers, which are negative for Cav1.2 and were used as staining control. Image from Eckhardt et al. 2019 in JGP https://bit.ly/2vZd6nE

We are pleased to present a collection of articles (https://bit.ly/2Rs9STG) on the structure, function and pharmacology ...
06/18/2019
Structure, function, and pharmacology of ion channels

We are pleased to present a collection of articles (https://bit.ly/2Rs9STG) on the structure, function and pharmacology of ion channels, which have been curated from recent issues of JGP and are freely available for a limited period.

Ion channels are transmembrane proteins that are critical components of both excitable and non-excitable cells. Without ion channels, neurons would not be able to communicate with other cells, muscle would not be able to contract and our immune system would not be able to fight infection. Indeed, wh...

Abbineni et al. (https://bit.ly/2Wrapuw) examined recent imaging work on fusion pores and discuss the dynamics of PI-4,5...
06/13/2019
Visualization of expanding fusion pores in secretory cells

Abbineni et al. (https://bit.ly/2Wrapuw) examined recent imaging work on fusion pores and discuss the dynamics of PI-4,5-P2 accumulation on granule membranes. #ThrowbackThursday

Secretory cells package their protein cargo into granules, which must fuse with the plasma membrane for these proteins to be released. Such exocytosis requires not only fusion of the granule membrane with the plasma membrane but also expansion of the fu...

Among the three two-pore channels (TPCs), TPC1 and TPC2 are selectively activated by PI(3,5)P2, while TPC3 has been cons...
06/12/2019
Phosphoinositides modulate the voltage dependence of two-pore channel 3

Among the three two-pore channels (TPCs), TPC1 and TPC2 are selectively activated by PI(3,5)P2, while TPC3 has been considered not to respond to any PIP2s. Shimomura and Kubo (https://bit.ly/2K9mXjT) find that TPC3 responds to both PI(3,5)P2 and PI(3,4)P2, but not to PI(4,5)P2.

Two-pore channels, or two-pore Na+ channels (TPCs), contain two homologous domains, each containing a functional unit typical of voltage-dependent cation channels. Each domain is considered to be responsible for either phosphoinositide (PI) binding or v...

We are pleased to present a collection of articles on excitatory synapses (https://bit.ly/2WzuKOw) that have been curate...
06/11/2019
Special Collection: Excitatory synapses

We are pleased to present a collection of articles on excitatory synapses (https://bit.ly/2WzuKOw) that have been curated from recent issues of JGP.

Excitatory synapses are the primary means by which information is communicated from one region of the central nervous system to another. Dynamic changes to their structure and molecular composition are associated with functional changes that underlie experience-dependent plasticity. Correspondingly,...

Edward Pugh (https://bit.ly/2WuiPBx) highlights recent work ruling out a role for ultraweak photon emission in spontaneo...
06/10/2019
The mechanism of photon-like dark noise in rod photoreceptors

Edward Pugh (https://bit.ly/2WuiPBx) highlights recent work ruling out a role for ultraweak photon emission in spontaneous photon-like events in retinal rods.

In absolute darkness, the CNG channel current of rod photoreceptor outer segments exhibits fluctuations. Some of the fluctuations, occurring about once per 100 s in mammalian rods, have a time course and amplitude that makes them indistinguishable from ...

Identification of the binding sites for small molecules that alleviate gating defects in CFTR would assist rational drug...
06/07/2019
Identifying the molecular target sites for CFTR potentiators GLPG1837 and VX-770

Identification of the binding sites for small molecules that alleviate gating defects in CFTR would assist rational drug design for the treatment of cystic fibrosis. Yeh et al. (https://bit.ly/2EUolCH) identify two potential binding sites for prototypical CFTR potentiators at the interface of CFTR’s two transmembrane domains.

The past two decades have witnessed major breakthroughs in developing compounds that target the chloride channel CFTR for the treatment of patients with cystic fibrosis. However, further improvement in affinity and efficacy for these CFTR modulators wil...

On the cover of JGP—Interfibrillar mitochondrial arrays in cardiac myocytes. The proton electrochemical potentials acr...
06/06/2019

On the cover of JGP—Interfibrillar mitochondrial arrays in cardiac myocytes. The proton electrochemical potentials across the mitochondrial inner membrane can be built through respiration involving the full or partial electron transfer chain, or the proton pumping activity of complex V operating in the ATPase mode. The charged mitochondria undergo intermittent and all-or-none electrochemical excitation in the form of "mitoflashes," which may serve to autoregulate mitochondrial proton electrochemical potential. Image from Feng et al. 2019 in JGP https://bit.ly/2WjDoAy

The latest issue of JGP features new research on mitoflash biogenesis, nicotine biosensors, cardiac currents, the human ...
06/06/2019

The latest issue of JGP features new research on mitoflash biogenesis, nicotine biosensors, cardiac currents, the human purinergic receptor P2X4, and more: https://bit.ly/2Wq9NWj

JGP poster award winners from the 2019 Biophysical Society of Canada Annual Meeting (from left to right): Daniel Nino, S...
06/05/2019

JGP poster award winners from the 2019 Biophysical Society of Canada Annual Meeting (from left to right): Daniel Nino, Sarah Bickers, and Rashik Ahmed.

On the cover of JGP—Interfibrillar mitochondrial arrays in cardiac myocytes. The proton electrochemical potentials acr...
06/05/2019

On the cover of JGP—Interfibrillar mitochondrial arrays in cardiac myocytes. The proton electrochemical potentials across the mitochondrial inner membrane can be built through respiration involving the full or partial electron transfer chain, or the proton pumping activity of complex V operating in the ATPase mode. The charged mitochondria undergo intermittent and all-or-none electrochemical excitation in the form of "mitoflashes," which may serve to autoregulate mitochondrial proton electrochemical potential. Image from Feng et al. 2019 in JGP https://bit.ly/2WjDoAy

Lactose permease must slide smoothly between at least two conformations, one open to the outside of the cell membrane an...
06/04/2019
It takes two to tango: The dance of the permease

Lactose permease must slide smoothly between at least two conformations, one open to the outside of the cell membrane and one open to the inside. This Viewpoint (https://bit.ly/2Ie8qjA) describes recent studies on the structure and mechanism lactose permease utilizes to perform its tango, a dance involving symport of an H+ and a sugar.

The lactose permease (LacY) of Escherichia coli is the prototype of the major facilitator superfamily, one of the largest families of membrane transport proteins. Structurally, two pseudo-symmetrical six-helix bundles surround a large internal aqueous c...

JGP poster award winners Jeong Joo Kim and Jennifer Noonan pictured with Vanathi Jayaraman (left) and Ryan Hibbs (right)...
06/03/2019

JGP poster award winners Jeong Joo Kim and Jennifer Noonan pictured with Vanathi Jayaraman (left) and Ryan Hibbs (right) at the CJM2 conference.

Read the editorial by JGP Editor-in-Chief Sharona Gordon “Excluding Scientist-Survivors from the NASEM Action Collabor...
05/30/2019
Excluding scientist survivors from the NASEM Action Collaborative is a step backward in changing culture to prevent sexual harassment

Read the editorial by JGP Editor-in-Chief Sharona Gordon “Excluding Scientist-Survivors from the NASEM Action Collaborative is a Step Backwards in Changing Culture to Prevent Sexual Harassment.”

The 2018 report from the National Academies of Sciences, Medicine, and Engineering (NASEM) on sexual harassment of women in academic sciences raised awareness in our community about the high prevalence of sexual harassment, the harm it causes, and the n...

Drugs that target insulin secretion are useful to understand β cell function and the pathogenesis of diabetes. Kalwat e...
05/30/2019
Chromomycin A2 potently inhibits glucose-stimulated insulin secretion from pancreatic β cells

Drugs that target insulin secretion are useful to understand β cell function and the pathogenesis of diabetes. Kalwat et al. (https://bit.ly/2JG8xYr) investigate an aureolic acid that inhibits insulin secretion and reveal that it disrupts Wnt signaling, interferes with gene expression, and suppresses Ca2+ influx in β cells. #ThrowbackThursday

Modulators of insulin secretion could be used to treat diabetes and as tools to investigate β cell regulatory pathways in order to increase our understanding of pancreatic islet function. Toward this goal, we previously used an insulin-linked luciferase...

P2X receptors (P2XRs) are ligand-gated cation channels involved in pain and inflammation. Gasparri et al. (https://bit.l...
05/29/2019
Molecular determinants for agonist recognition and discrimination in P2X2 receptors

P2X receptors (P2XRs) are ligand-gated cation channels involved in pain and inflammation. Gasparri et al. (https://bit.ly/2YQAuQD) show that the backbone carbonyl atoms of amino acid residue Thr184 are involved in ligand discrimination, while those of Lys69 contribute mostly to ligand recognition by rat P2X2Rs.

P2X receptors (P2XRs) are trimeric ligand-gated ion channels that open a cation-selective pore in response to ATP binding. P2XRs contribute to synaptic transmission and are involved in pain and inflammation, thus representing valuable drug targets. Rece...

This year's Knox Chandler Awards at the GRS/GRC 2019 meeting on Muscle: Excitation-Contraction Coupling were Michelle Mu...
05/28/2019

This year's Knox Chandler Awards at the GRS/GRC 2019 meeting on Muscle: Excitation-Contraction Coupling were Michelle Munro, Graciano Leal, Daniel Blackwell, Roberto Silva-Rojas. In the photo from left to right: Michael Fill, Carlo Manno, Amy Hanna, Michelle Munro, Graciano Leal, Daniel Blackwell, Roberto Silva-Rojas and Filip Van Petegem.

Olfactory responses in the cilia of olfactory receptor cells last for longer than 10 s, which cannot be explained by fre...
05/23/2019
Second messenger molecules have a limited spread in olfactory cilia

Olfactory responses in the cilia of olfactory receptor cells last for longer than 10 s, which cannot be explained by free diffusion of second messengers. Takeuchi and Kurahashi (https://bit.ly/2Etk3C3) show that these signaling molecules have a limited spread and remain at the site of generation for a long time. #ThrowbackThursday

Odorants are detected by olfactory receptors on the sensory cilia of olfactory receptor cells (ORCs). These cylindrical cilia have a diameters of 100–200 nm, within which the components required for signal transduction by the adenylyl cyclase–cAMP syste...

We are pleased to present a collection of articles on ligand-gated ion channels that have been curated from recent issue...
05/20/2019
Ligand-gated ion channels

We are pleased to present a collection of articles on ligand-gated ion channels that have been curated from recent issues of JGP (https://bit.ly/2Em80GF). Along with cutting-edge Research Articles on the structure and function of glutamate-, acetylcholine-, and ATP-gated ion channels, the collection features a Hypothesis on allosteric regulation of ion channel function by the lipid membrane and a Review of our current understanding of NMDA receptors.

Ligand-gated ion channels are membrane proteins that transduce the binding of a ligand, such as a neurotransmitter, into an electrical response. In recent years, our understanding of the mechanisms by which ligands bind to and open these ion channels has been revolutionized by advances in structural...

Extraocular muscles are specialized skeletal muscles expressing a particular set of proteins involved in calcium homeost...
05/15/2019
Extraocular muscle function is impaired in ryr3−/− mice

Extraocular muscles are specialized skeletal muscles expressing a particular set of proteins involved in calcium homeostasis, including RYR3. Eckhardt et al. (https://bit.ly/2vZd6nE) investigate extraocular muscle function in ryr3−/− mice and show that ablation of RYR3 significantly impacts vision.

Calcium is an ubiquitous second messenger mediating numerous physiological processes, including muscle contraction and neuronal excitability. Ca2+ is stored in the ER/SR and is released into the cytoplasm via the opening of intracellular inositol trisph...

A JGP paper by Abu-Arish et al. (https://bit.ly/2vGQiZS) details some unexpected findings regarding CFTR distribution an...
05/14/2019
CFTR gets together

A JGP paper by Abu-Arish et al. (https://bit.ly/2vGQiZS) details some unexpected findings regarding CFTR distribution and dynamics in the plasma membrane.

JGP study shows that pro-secretory agonists prompt CFTR to assemble into large lipid platforms.

Our latest issue features new research on contractility of striated muscle, myofilament force, mechanical stiffness in m...
05/10/2019

Our latest issue features new research on contractility of striated muscle, myofilament force, mechanical stiffness in muscle, and more: https://bit.ly/2Yl71hE

On the cover of JGP—The actin-capping protein CapZ integrates mechanosignaling pathways, such as phosphorylation and p...
05/09/2019

On the cover of JGP—The actin-capping protein CapZ integrates mechanosignaling pathways, such as phosphorylation and phosphatidylinositol 4,5-bisphosphate (PIP2) binding, to regulate muscle growth in response to mechanical loading by substrates of varying stiffness. Here, PIP2 is localized to the Z-disks of a neonatal rat ventricular myocyte grown on a stiff glass substrate, fixed and stained for α-actinin (red) and PIP2 (green). Results show the C-terminal domain of the CapZβ1 subunit stabilizes CapZ and PIP2 interactions, which may have relevance to fibrotic heart disease. Image from Solís and Russell https://bit.ly/2vPvuzr

On the cover of JGP—The actin-capping protein CapZ integrates mechanosignaling pathways, such as phosphorylation and p...
05/08/2019

On the cover of JGP—The actin-capping protein CapZ integrates mechanosignaling pathways, such as phosphorylation and phosphatidylinositol 4,5-bisphosphate (PIP2) binding, to regulate muscle growth in response to mechanical loading by substrates of varying stiffness. Here, PIP2 is localized to the Z-disks of a neonatal rat ventricular myocyte grown on a stiff glass substrate, fixed and stained for α-actinin (red) and PIP2 (green). Results show the C-terminal domain of the CapZβ1 subunit stabilizes CapZ and PIP2 interactions, which may have relevance to fibrotic heart disease. Image from Solís and Russell https://bit.ly/2vPvuzr

Glial-like supporting cells of the olfactory epithelium are involved in a variety of processes important to the function...
05/08/2019
TMEM16A calcium-activated chloride currents in supporting cells of the mouse olfactory epithelium

Glial-like supporting cells of the olfactory epithelium are involved in a variety of processes important to the function of this tissue. Henriques et al. (https://bit.ly/2DTq6PZ) find that supporting cells exhibit an ATP-induced, Ca2+-sensitive Cl− current produced by TMEM16A Cl− channels.

Glial-like supporting (or sustentacular) cells are important constituents of the olfactory epithelium that are involved in several physiological processes such as production of endocannabinoids, insulin, and ATP and regulation of the ionic composition o...

Little is known about how CFTR, the Cl− channel that is mutated in cystic fibrosis, interacts with lipids. Abu-Arish e...
05/07/2019
Agonists that stimulate secretion promote the recruitment of CFTR into membrane lipid microdomains

Little is known about how CFTR, the Cl− channel that is mutated in cystic fibrosis, interacts with lipids. Abu-Arish et al. (https://bit.ly/2vGQiZS) show that agents that stimulate salt and fluid secretion reduce CFTR lateral mobility and promote its clustering into ceramide-rich platforms, thereby increasing its surface expression.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a tightly regulated anion channel that mediates secretion by epithelia and is mutated in the disease cystic fibrosis. CFTR forms macromolecular complexes with many proteins; however, litt...

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