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.
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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.

The auxiliary proteins CaM and FHF bind to the C-terminal domain of voltage-gated sodium channels to limit the persisten...
01/03/2020
An interaction between the III-IV linker and CTD in NaV1.5 confers regulation of inactivation by CaM and FHF

The auxiliary proteins CaM and FHF bind to the C-terminal domain of voltage-gated sodium channels to limit the persistent inward currents associated with cardiac arrhythmias. Aravind R. Gade, Steven O. Marx, and Geoffrey S. Pitt reveal (https://bit.ly/2FbjjkQ) that CaM and FHF exert their effects by stabilizing an interaction between the channel’s C-terminal domain and III-IV linker region.

Voltage gated sodium channel (VGSC) activation drives the action potential upstroke in cardiac myocytes, skeletal muscles, and neurons.

Briana M. Bohannon, H. Peter Larsson, and colleagues (https://bit.ly/2QB4Qnz) show that polyunsaturated fatty acids (PUF...
01/02/2020
Polyunsaturated fatty acids produce a range of activators for heterogeneous IKs channel dysfunction

Briana M. Bohannon, H. Peter Larsson, and colleagues (https://bit.ly/2QB4Qnz) show that polyunsaturated fatty acids (PUFAs) vary in their ability to activate cardiac IKs potassium channels depending on the pKa of the PUFA head group, allowing PUFAs to be tuned to treat long QT syndrome mutants with different disease severity.

Repolarization and termination of the ventricular cardiac action potential is highly dependent on the activation of the slow delayed-rectifier potassium IKs channel.

Exciting changes came to Rockefeller University Press journals this year, including the launch of the new Journal of Cel...
12/24/2019

Exciting changes came to Rockefeller University Press journals this year, including the launch of the new Journal of Cell Biology (JCB), Journal of Experimental Medicine (JEM), and Journal of General Physiology (JGP) websites on the Silverchair platform. Our first priority is to serve the scientific community, and our new websites ensure that we meet this commitment by providing an excellent reading experience through cutting edge functionality. If you haven’t yet, we encourage you to try the new Split-Screen View feature and leave us your feedback through our survey (https://bit.ly/2EOFDAA).

Thank you for trusting JCB, JEM, JGP, and Life Science Alliance (LSA) as resources for your work, submitting your best research, and helping to make the journals truly representative of the broad community of scientists we aim to serve.

Toshiko Yamazawa, Masamitsu Iino, and colleagues (https://bit.ly/36PmSJv) studied the molecular bases of pathogenic enha...
12/18/2019
Insights into channel modulation mechanism of RYR1 mutants using Ca2+ imaging and molecular dynamics

Toshiko Yamazawa, Masamitsu Iino, and colleagues (https://bit.ly/36PmSJv) studied the molecular bases of pathogenic enhancement of Ca2+ release channel activities in RYR1 carrying disease-associated mutations at the N-terminal region.

Type 1 ryanodine receptor (RYR1) is a Ca2+ release channel in the sarcoplasmic reticulum in skeletal muscle and plays an important role in excitation–contraction coupling.

Elisa Carrillo, Sana Shaikh, Vasanthi Jayaraman, and colleagues (https://bit.ly/2sAKjak) use single molecule approaches ...
12/17/2019
Resensitizing AMPA receptors

Elisa Carrillo, Sana Shaikh, Vasanthi Jayaraman, and colleagues (https://bit.ly/2sAKjak) use single molecule approaches to provide new insights into how γ8 induces this receptor resensitization. Read more in Research News: https://bit.ly/2PTZlAl

JGP study suggests how the regulatory protein γ8 reopens AMPA receptor channels in the continued presence of glutamate.

On the cover of JGP—Secretory vesicles containing MMP9-GFP near the plasma membrane of MCF-7 breast cancer cells. Overla...
12/13/2019

On the cover of JGP—Secretory vesicles containing MMP9-GFP near the plasma membrane of MCF-7 breast cancer cells. Overlay of TIRF MMP9-GFP image (green) and platinum replica TEM image (gray) of a MCF-7 cell plasma membrane sheet. Note the presence of other unlabeled membrane structures found on the MCF-7 cell membrane (e.g., actin filaments are visible all around the secretory vesicles). Image © Stephens et al., 2019 https://bit.ly/34gh8Xf

JGP, in partnership with the Society for General Physiologists, is now accepting applications for the 2019 Junior Facult...
12/13/2019
Junior Faculty Networking Cohort

JGP, in partnership with the Society for General Physiologists, is now accepting applications for the 2019 Junior Faculty Networking Cohort (https://bit.ly/2EgPzmo). The program is designed to support and connect junior faculty in the first stage of their independent careers. Up to nine junior faculty will be matched with JGP Editorial Advisory Board Member Robert J. French, PhD, for group discussions. Each discussion begins with a topic of relevance, such as selecting and managing personnel, financial management, and collaborating wisely.

JGP, in partnership with the Society of General Physiologists, has launched the Junior Faculty Networking Cohort, a program designed to support and connect junior faculty i...

Michael Grabe, Daniel M. Zuckerman, and John M. Rosenberg provide commentary (https://bit.ly/2Pf9ZTb) on a new study by ...
12/13/2019
EmrE reminds us to expect the unexpected in membrane transport

Michael Grabe, Daniel M. Zuckerman, and John M. Rosenberg provide commentary (https://bit.ly/2Pf9ZTb) on a new study by Grant A. Hussey and colleagues (https://bit.ly/34bIbDc) that describes a new mathematical model of the EmrE multidrug efflux pump.

Have we been projecting “mechanomorphic” ideas onto molecular machines? That is, has our description of these amazing devices been unduly biased by human ideas of machine design?

On the cover of JGP—Secretory vesicles containing MMP9-GFP near the plasma membrane of MCF-7 breast cancer cells. Overla...
12/12/2019

On the cover of JGP—Secretory vesicles containing MMP9-GFP near the plasma membrane of MCF-7 breast cancer cells. Overlay of TIRF MMP9-GFP image (green) and platinum replica TEM image (gray) of a MCF-7 cell plasma membrane sheet. Note the presence of other unlabeled membrane structures found on the MCF-7 cell membrane (e.g., actin filaments are visible all around the secretory vesicles). Image © Stephens et al., 2019 https://bit.ly/34gh8Xf

CRAC channels contain a cluster of positively charged residues in the inner pore whose function is not understood. Here,...
12/12/2019
The basic residues in the Orai1 channel inner pore promote opening of the outer hydrophobic gate | The Journal of General Physiology | Rockefeller University Press

CRAC channels contain a cluster of positively charged residues in the inner pore whose function is not understood. Here, Megumi Yamash*ta, Murali Prakriya and colleagues (https://bit.ly/2rAKtP3) show that these positive charges promote pore opening by enhancing hydration of the hydrophobic gate located at the outer end of the pore.

Store-operated Orai1 channels regulate a wide range of cellular functions from gene expression to cell proliferation. Previous studies have shown that gating of Orai1 channels is regulated by the outer pore residues V102 and F99, which together function as a hydrophobic gate to block ion conduction ...

Secondary active transport mechanisms often depict a limited number of states and transitions, although recent research ...
12/11/2019
Highly coupled transport can be achieved in free-exchange transport models | The Journal of General Physiology | Rockefeller University Press

Secondary active transport mechanisms often depict a limited number of states and transitions, although recent research suggests that alternative “leak” pathways are not always minor. Grant A. Hussey, Nathan E. Thomas, and Katherine A. Henzler-Wildman (https://bit.ly/34bIbDc) numerically simulate a fully unrestricted model for the bacterial transporter EmrE and demonstrate that highly efficient transport can be achieved despite the existence of multiple leak pathways.

Secondary active transporters couple the transport of an ion species down its concentration gradient to the uphill transport of another substrate. Despite the importance of secondary active transport to multidrug resistance, metabolite transport, and nutrient acquisition, among other biological proc...

Much of what is known today about the health risks associated with tobacco smoke and high levels of cholesterol in the b...
12/10/2019
Science history: Marie Maynard Daly, lifesaver

Much of what is known today about the health risks associated with tobacco smoke and high levels of cholesterol in the blood began with the work of Marie Maynard Daly. Some of her work was published in JGP between 1949 and 1955. https://bit.ly/345Qj8n

Chemist helped highlight the dangers of cholesterol and tobacco.

Using single-channel recordings and single-molecule FRET, Elisa Carrillo, Vasanthi Jayaraman, and colleagues (https://bi...
11/27/2019
Mechanism of modulation of AMPA receptors by TARP-γ8

Using single-channel recordings and single-molecule FRET, Elisa Carrillo, Vasanthi Jayaraman, and colleagues (https://bit.ly/2XMMcMF) show that resensitization of AMPA receptors by the regulatory protein γ8 is characterized by transitions to high conductance levels associated with tighter conformational coupling similar to those seen in the presence of cyclothiazide.

Fast excitatory synaptic transmission in the mammalian central nervous system is mediated by glutamate-activated α-amino-5-methyl-3-hydroxy-4-isoxazole propionate (AMPA) receptors. In neurons, AMPA receptors coassemble with transmembrane AMPA receptor r...

Potassium ion conduction through open potassium channels is essential to control of membrane potentials in all cells. To...
11/26/2019

Potassium ion conduction through open potassium channels is essential to control of membrane potentials in all cells. To elucidate the open conformation and hence the mechanism of K+ ion conduction in the classic inward rectifier Kir2.2, Zangerl-Plessl et al. introduced a negative charge (G178D) at the crossing point of the inner helix bundle, the location of ligand-dependent gating. This “forced open” mutation generated channels that were active even in the complete absence of phosphatidylinositol-4,5-bisphosphate (PIP2), an otherwise essential ligand for Kir channel opening. This image shows crystal structures of forced open mutant channels in both the absence (Apo-KW/GD, yellow) and presence (PIP2-KW/GD, orange) of PIP2. Image © Zangerl-Plessl et al. 2019 in JGP https://bit.ly/2Xv9NBq

Richard L. Moss considers recent work by Marco Caremani, Massimo Reconditi, and colleagues (https://bit.ly/2qjTawF) desc...
11/22/2019
A case for reduced energy utilization associated with spatial disorder of myosin in skeletal muscle

Richard L. Moss considers recent work by Marco Caremani, Massimo Reconditi, and colleagues (https://bit.ly/2qjTawF) describing the effect of low temperature on force development in skeletal muscle. https://bit.ly/2KFohth

For decades, regulation of the force developed by striated muscles has been thought to principally or solely involve the delivery of Ca2+ to the myoplasm. Increases in free myoplasmic [Ca2+] result in activation of the thin filament due to Ca2+ binding ...

This paper by Eva-Maria Zangerl-Plessl, Colin G. Nichols, and colleagues (https://bit.ly/2Xv9NBq) presents the crystal s...
11/21/2019
Atomistic basis of opening and conduction in mammalian inward rectifier potassium (Kir2.2) channels

This paper by Eva-Maria Zangerl-Plessl, Colin G. Nichols, and colleagues (https://bit.ly/2Xv9NBq) presents the crystal structure of a forced open inward rectifier Kir2.2 channel. Molecular dynamics reveals the details of ion permeation through the open channel.

Potassium ion conduction through open potassium channels is essential to control of membrane potentials in all cells. To elucidate the open conformation and hence the mechanism of K+ ion conduction in the classic inward rectifier Kir2.2, we introduced a...

This paper by Eva-Maria Zangerl-Plessl, Colin G. Nichols, and colleagues (https://bit.ly/2Xv9NBq) presents the crystal s...
11/21/2019
Atomistic basis of opening and conduction in mammalian inward rectifier potassium (Kir2.2) channels

This paper by Eva-Maria Zangerl-Plessl, Colin G. Nichols, and colleagues (https://bit.ly/2Xv9NBq) presents the crystal structure of a forced open inward rectifier Kir2.2 channel. Molecular dynamics reveals the details of ion permeation through the open channel.

Potassium ion conduction through open potassium channels is essential to control of membrane potentials in all cells. To elucidate the open conformation and hence the mechanism of K+ ion conduction in the classic inward rectifier Kir2.2, we introduced a...

A JGP study by Dominique C. Stephens, Dinari A. Harris, and colleagues (https://bit.ly/34BJUCz) describes the spatiotemp...
11/18/2019
Determining the dynamics of cancer cell secretion

A JGP study by Dominique C. Stephens, Dinari A. Harris, and colleagues (https://bit.ly/34BJUCz) describes the spatiotemporal dynamics of proteins and lipids involved in the exocytosis of the matrix metalloproteinase MMP-9 from breast cancer cells. Read a highlight in the latest Research News: https://bit.ly/2CCcEz5

JGP study describes the spatiotemporal dynamics of proteins and lipids involved in the exocytosis of the matrix metalloproteinase MMP-9 from breast cancer cells.

We are pleased to present a collection of Reviews (https://bit.ly/2WDiIjR) on the structure and function of ion channels...
11/15/2019
JGP Reviews: Ion Channel Structure and Function

We are pleased to present a collection of Reviews (https://bit.ly/2WDiIjR) on the structure and function of ion channels, which have been curated from recent issues of JGP for their relevance to The Austin Conference on Ion Channel Dynamics and Mechanisms.

Ion channels are proteins that are present in the membranes of virtually all living cells. They transport charged ions from one side of a membrane to the other, thus their activity can be observed with electrical recording techniques. The first recordings of single ion channels openings were publish...

John M. Squire and Pradeep K. Luther consider new evidence for a simple lattice structure in mammalian skeletal muscle f...
11/14/2019
Mammalian muscle fibers may be simple as well as slow

John M. Squire and Pradeep K. Luther consider new evidence for a simple lattice structure in mammalian skeletal muscle from Weikang Ma, Roger Craig, and colleagues (https://bit.ly/36Vx6sG). https://bit.ly/33WkUWo

One of the thrills of science is when a discovery made long ago, and nearly forgotten, gets picked up when viewing it from a new perspective and receives a whole new lease on life. The lattice arrangement of myosin filaments in vertebrate striated muscl...

On the cover of JGP—Fluorescence Lifetime Imaging (FLIM) reveals distinct differences in the sodium concentration of the...
11/13/2019

On the cover of JGP—Fluorescence Lifetime Imaging (FLIM) reveals distinct differences in the sodium concentration of the nucleus, perinuclear regions, and cytosol of human embryonic kidney cells (HEK293T). The cells were stained with the sodium-sensitive dye CoroNaGreen AM; the color-coded image indicates low sodium levels in blue, and increasing sodium levels are indicated by a shift to green-yellow-red. Image © Meyer et al., 2019 https://bit.ly/33r9lX8

The latest issue of JGP features new research on myosin activation, cone photoreceptors, sodium current in Purkinje cell...
11/12/2019

The latest issue of JGP features new research on myosin activation, cone photoreceptors, sodium current in Purkinje cells, and more: https://bit.ly/34UaIy6

Weikang Ma, Roger Craig, and colleagues (https://bit.ly/36Vx6sG) studied the 3-D arrangement of thick filaments in skele...
11/11/2019
Lattice arrangement of myosin filaments correlates with fiber type in rat skeletal muscle

Weikang Ma, Roger Craig, and colleagues (https://bit.ly/36Vx6sG) studied the 3-D arrangement of thick filaments in skeletal muscle by x-ray diffraction and electron microscopy and found a correlation between thick filament lattice type (simple or superlattice) and fiber type (fast/slow). This suggests that lattice organization contributes to muscle functional properties.

The thick (myosin-containing) filaments of vertebrate skeletal muscle are arranged in a hexagonal lattice, interleaved with an array of thin (actin-containing) filaments with which they interact to produce contraction. X-ray diffraction and EM have show...

On the cover of JGP—Fluorescence Lifetime Imaging (FLIM) reveals distinct differences in the sodium concentration of the...
11/08/2019

On the cover of JGP—Fluorescence Lifetime Imaging (FLIM) reveals distinct differences in the sodium concentration of the nucleus, perinuclear regions, and cytosol of human embryonic kidney cells (HEK293T). The cells were stained with the sodium-sensitive dye CoroNaGreen AM; the color-coded image indicates low sodium levels in blue, and increasing sodium levels are indicated by a shift to green-yellow-red. Image © Meyer et al., 2019 https://bit.ly/33r9lX8

Gary Rudnick highlights research by Aaron T. Bozzi, Rachelle Gaudet, and colleagues (https://bit.ly/35EZ7UC), who perfor...
11/08/2019
Unconventional transport of metal ions and protons by Nramps

Gary Rudnick highlights research by Aaron T. Bozzi, Rachelle Gaudet, and colleagues (https://bit.ly/35EZ7UC), who performed a kinetic analysis of a bacterial Nramp transporter that focuses on how H+ gradients are coupled to metal transport.

Nramps are divalent transition metal ion transporters found in essentially all organisms from prokaryotes to mammals ([Nevo and Nelson, 2006][1]). The name Nramp comes from natural resistance-associated macrophage protein, because it was first identifie...

This paper describes the dynamics of proteins and lipids during exocytosis of MMP-9 from cancer cells in real time using...
11/07/2019
Spatiotemporal organization and protein dynamics involved in regulated exocytosis of MMP-9 in breast cancer cells

This paper describes the dynamics of proteins and lipids during exocytosis of MMP-9 from cancer cells in real time using fluorescence microscopy. Dominique C. Stephens, Dinari A. Harris, and colleagues (https://bit.ly/34BJUCz) find that core exocytic proteins, accessory proteins, and lipids are involved at sites of secretory vesicle fusion.

Altered regulation of exocytosis is an important mechanism controlling many diseases, including cancer. Defects in exocytosis have been implicated in many cancer cell types and are generally attributed to mutations in cellular transport, trafficking, an...

Cochlear amplification is mediated by the outer hair cell of the organ of Corti. Joseph Santos-Sacchi, Kuni H. Iwasa and...
11/06/2019
Outer hair cell electromotility is low-pass filtered relative to the molecular conformational changes that produce nonlinear capacitance

Cochlear amplification is mediated by the outer hair cell of the organ of Corti. Joseph Santos-Sacchi, Kuni H. Iwasa and Winston Tan (https://bit.ly/2oObm0r) reveal that the cell possesses a voltage-dependent motile frequency response that differs from that of its voltage sensor/effector, the electromotile protein prestin, implying variable coupling between the two.

The outer hair cell (OHC) of the organ of Corti underlies a process that enhances hearing, termed cochlear amplification. The cell possesses a unique voltage-sensing protein, prestin, that changes conformation to cause cell length changes, a process ter...

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