Author Response: A computational model predicts sex-specific responses to calcium channel blockers in mesenteric vascular smooth muscle DOI Open Access
Gonzalo Hernandez-Hernandez, Samantha C. O’Dwyer, Collin Matsumoto

et al.

Published: Dec. 20, 2023

The function of the smooth muscle cells lining walls systemic arteries and arterioles is to regulate diameter vessels control blood flow pressure. Here, we describe an in-silico model, which call "Hernandez-Hernandez model", electrical Ca2+ signaling in arterial myocytes based on new experimental data indicating sex-specific differences male female from resistance arteries. model suggests fundamental ionic mechanisms underlying membrane potential intracellular during development myogenic tone vessels. Although suggest that KV1.5 channel currents have similar amplitudes, kinetics, voltage dependencies myocytes, simulations current dominant regulating myocytes. In cells, larger KV2.1 expression longer time constants for activation than predictions simulated plays a primary role potential. Over physiological range potentials, gating small number voltage-gated K+ channels L-type are predicted drive excitability. We also show idealized computational vessel, exhibits heightened sensitivity commonly used blockers compared male. summary, present framework investigate impact anti-hypertensive drugs.

Language: Английский

Interstitial cells of Cajal – pacemakers of the gastrointestinal tract DOI
Kenton M. Sanders, Luis F. Santana, Salah A. Baker

et al.

The Journal of Physiology, Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 23, 2023

Abstract Gastrointestinal (GI) organs display spontaneous, non‐neurogenic electrical, and mechanical rhythmicity that underlies fundamental motility patterns, such as peristalsis segmentation. Electrical (aka slow waves) results from pacemaker activity generated by interstitial cells of Cajal (ICC). ICC express a unique set ionic conductances Ca 2+ handling mechanisms generate actively propagate waves. GI smooth muscle lack these conductances. Slow waves within networks conduct electrotonically to via gap junctions. depolarize activate voltage‐dependent channels (predominantly CaV1.2), causing influx excitation–contraction coupling. The main responsible for in are ANO1, ‐activated Cl − conductance, CaV3.2. cycle, currently understood, begins with localized release events spontaneous transient inward currents due activation ANO1 channels. Depolarization activates V 3.2 channels, the upstroke depolarization phase is followed long‐duration plateau can last several seconds. ‐induced temporal cluster transients sustains clamps membrane potential near equilibrium ions. ends, repolarization occurs, when stores depleted, ceases deactivate. This review summarizes key electrical gastrointestinal organs. image

Language: Английский

Citations

19
Endoplasmic Reticulum–Plasma Membrane Junctions as Sites of Depolarization-Induced Ca2+Signaling in Excitable Cells DOI Creative Commons
Rose E. Dixon, James S. Trimmer

Annual Review of Physiology, Journal Year: 2022, Volume and Issue: 85(1), P. 217 - 243

Published: Oct. 6, 2022

Membrane contact sites between endoplasmic reticulum (ER) and plasma membrane (PM), or ER-PM junctions, are found in all eukaryotic cells. In excitable cells they play unique roles organizing diverse forms of Ca

Language: Английский

Citations

24
What makes the sinoatrial node tick? A question not for the faint of heart DOI Creative Commons
Lorenzo A. H. Donald, Edward G. Lakatta

Philosophical Transactions of the Royal Society B Biological Sciences, Journal Year: 2023, Volume and Issue: 378(1879)

Published: May 1, 2023

Even before the sinoatrial node (SAN) was discovered, cardiovascular science engaged in an active investigation of when and why heart would beat. After electrochemical theory bioelectric membrane potentials formulated first action were measured contracting muscle cells, field became divided: some investigators studied electrophysiology ion channels, others contraction. It later known that changes intracellular Ca 2+ cause The pacemaking reunited by coupled-clock pacemaker cell function, which integrated cycling transmembrane voltage into one rhythmogenic system. In this review, we will discuss recent discoveries contextualize system, described isolated SAN complex world tissue: heterogeneous local releases, generated within cells regulated other types cytoarchitecture, variably co-localize synchronize to give rise relatively rhythmic impulses emanate from excite heart. We ultimately conceptualize as a brain-like structure, composed intercommunicating meshworks multiple interstitial intertwined networks nerves glial more. This article is part theme issue ‘The heartbeat: its molecular basis physiological mechanisms’.

Language: Английский

Citations

13
Non-ionotropic voltage-gated calcium channel signaling DOI Creative Commons

Michael Trus,

Daphné Atlas

Channels, Journal Year: 2024, Volume and Issue: 18(1)

Published: April 11, 2024

Voltage-gated calcium channels (VGCCs) are the major conduits for ions (Ca2+) within excitable cells. Recent studies have highlighted non-ionotropic functionality of VGCCs, revealing their capacity to activate intracellular pathways independently ion flow. This signaling mode plays a pivotal role in excitation-coupling processes, including gene transcription through excitation-transcription (ET), synaptic transmission via excitation-secretion (ES), and cardiac contraction excitation-contraction (EC). However, it is noteworthy that these processes require extracellular Ca2+ occupancy channel pore. Analogous "non-canonical" characterization exhibited by N-methyl-D-aspartate receptor (NMDA), which requires without influx ions, VGCC activation depolarization-triggered conformational change(s) concomitant with binding open channel. Here, we discuss contributions VGCCs ES, ET, EC coupling as macromolecules transduces external stimuli input prior elevating Ca2+. We emphasize recognition ion-pore its contribution excitation precede calcium. The triggered upstroke an action potential, provides conceptual framework elucidate mechanistic aspects underlying microseconds nature transmission, contractility, rapid induction first-wave genes.

Language: Английский

Citations

4
The formation of KV2.1 macro-clusters is required for sex-specific differences in L-type CaV1.2 clustering and function in arterial myocytes DOI Creative Commons
Collin Matsumoto, Samantha C. O’Dwyer, Declan Manning

et al.

Communications Biology, Journal Year: 2023, Volume and Issue: 6(1)

Published: Nov. 14, 2023

In arterial myocytes, the canonical function of voltage-gated Ca

Language: Английский

Citations

8
KairoSight-3.0: A validated optical mapping software to characterize cardiac electrophysiology, excitation-contraction coupling, and alternans DOI Creative Commons

Kazi T. Haq,

Anysja Roberts,

Fiona Berk

et al.

Journal of Molecular and Cellular Cardiology Plus, Journal Year: 2023, Volume and Issue: 5, P. 100043 - 100043

Published: Aug. 18, 2023

Cardiac optical mapping is an imaging technique that measures fluorescent signals across a cardiac preparation. Dual of voltage-sensitive and calcium-sensitive probes allows for simultaneous recordings action potentials intracellular calcium transients with high spatiotemporal resolution. The analysis these complex datasets both time intensive technically challenging; as such, we have developed software package semi-automated image processing analysis. Herein, report updated version our (KairoSight-3.0) features to enhance the characterization parameters using signals.To test validity applicability, used Langendorff-perfused heart preparations record transmembrane voltage from epicardial surface. Isolated hearts guinea pigs rats were loaded potentiometric dye (RH237) and/or indicator (Rhod-2AM) acquired. We Python 3.8.5 programming language develop KairoSight-3.0 software. maps validated user-specified manual approach.Manual potential duration (30 or 80 % repolarization), transient reuptake), alternans constituted validate accuracy software-generated maps. Manual had accuracy, >97 values falling within 10 ms each other >75 5 measurements (n = 1000-2000 pixels). Further, includes additional measurement tools analyze signal-to-noise ratio, conduction velocity, alternans, potential-calcium coupling produce physiologically meaningful maps.KairoSight-3.0 has enhanced capabilities perform electrophysiology, handling, excitation-contraction satisfactory accuracy.

Language: Английский

Citations

6
Disorder in Ca2+ release unit locations confers robustness but cuts flexibility of heart pacemaking DOI Creative Commons
Anna Maltsev, Michael D. Stern, Victor A. Maltsev

et al.

The Journal of General Physiology, Journal Year: 2022, Volume and Issue: 154(9)

Published: Aug. 9, 2022

Excitation-contraction coupling kinetics is dictated by the action potential rate of sinoatrial-nodal cells. These cells generate local Ca releases (LCRs) that activate Na/Ca exchanger current, which accelerates diastolic depolarization and determines pace. LCRs are generated clusters ryanodine receptors, release units (CRUs), residing in sarcoplasmic reticulum. While CRU distribution exhibits substantial heterogeneity, its functional importance remains unknown. Using numerical modeling, here we show with a square lattice CRUs, Ca-induced-Ca-release propagation during insufficient for pacemaking within broad range realistic ICaL densities. Allowing each to deviate randomly from position allows sparks propagate, as observed experimentally. As disorder increases, larger empty spaces simultaneously clusters, Poisson clumping. Propagating becomes synchronized, increasing reviving pacemaker function dormant/nonfiring However, fully disordered positions could not reach low firing rates their β-adrenergic-receptor stimulation effect was substantially decreased. Inclusion Cav1.3, low-voltage activation L-type channel isoform into ICaL, strongly increases recruitment CRUs fire depolarization, robustness complementing effects distribution. Thus, order/disorder locations along Cav1.3 expression regulates via synchronization firing. Excessive and/or overexpression boosts basal state, but limits range, may contribute heart decline age disease.

Language: Английский

Citations

10
A computational model predicts sex-specific responses to calcium channel blockers in mammalian mesenteric vascular smooth muscle DOI Creative Commons
Gonzalo Hernandez-Hernandez, Samantha C. O’Dwyer, Pei‐Chi Yang

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Sept. 12, 2023

The function of the smooth muscle cells lining walls mammalian systemic arteries and arterioles is to regulate diameter vessels control blood flow pressure. Here, we describe an in silico model, which call ‘Hernandez–Hernandez model’, electrical Ca 2+ signaling arterial myocytes based on new experimental data indicating sex-specific differences male female from murine resistance arteries. model suggests fundamental ionic mechanisms underlying membrane potential intracellular during development myogenic tone vessels. Although suggest that K V 1.5 channel currents have similar amplitudes, kinetics, voltage dependencies myocytes, simulations current dominant regulating myocytes. In cells, larger 2.1 expression longer time constants for activation than predictions simulated plays a primary role potential. Over physiological range potentials, gating small number voltage-gated + channels L-type are predicted drive excitability. We also show idealized computational vessel, exhibits heightened sensitivity commonly used blockers compared male. summary, present framework investigate impact antihypertensive drugs.

Language: Английский

Citations

5
Augmenting workload drives T‐tubule assembly in developing cardiomyocytes DOI Creative Commons
Ornella Manfra, Samantha Louey, Sonnet S. Jonker

et al.

The Journal of Physiology, Journal Year: 2023, Volume and Issue: 602(18), P. 4461 - 4486

Published: May 2, 2023

Contraction of cardiomyocytes is initiated at subcellular elements called dyads, where L-type Ca

Language: Английский

Citations

5
A computational model predicts sex-specific responses to calcium channel blockers in mammalian mesenteric vascular smooth muscle DOI Creative Commons
Gonzalo Hernandez-Hernandez, Samantha C. O’Dwyer, Pei‐Chi Yang

et al.

eLife, Journal Year: 2024, Volume and Issue: 12

Published: Feb. 9, 2024

The function of the smooth muscle cells lining walls mammalian systemic arteries and arterioles is to regulate diameter vessels control blood flow pressure. Here, we describe an in silico model, which call ‘Hernandez–Hernandez model’, electrical Ca 2+ signaling arterial myocytes based on new experimental data indicating sex-specific differences male female from murine resistance arteries. model suggests fundamental ionic mechanisms underlying membrane potential intracellular during development myogenic tone vessels. Although suggest that K V 1.5 channel currents have similar amplitudes, kinetics, voltage dependencies myocytes, simulations current dominant regulating myocytes. In cells, larger 2.1 expression longer time constants for activation than predictions simulated plays a primary role potential. Over physiological range potentials, gating small number voltage-gated + channels L-type are predicted drive excitability. We also show idealized computational vessel, exhibits heightened sensitivity commonly used blockers compared male. summary, present framework investigate impact antihypertensive drugs.

Language: Английский

Citations

1