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961.
1. Experimental findings in the past decade have greatly advanced present understanding of electrical/mechanical rhythmicities in smooth muscle, including vasomotion. Lymphatic vessels show strong vasomotor activity and have provided a key experimental system to study these processes. 2. Evidence from lymphatic vessels, blood vessels and other smooth muscles indicates that rhythmical contractions arise through a Ca2+ store-controlled pacemaker mechanism, which can function to cause smooth muscle constriction. 3. Such a model fits with observations that vasomotion can be near synchronous over large vessel lengths involving many cells. 4. The alternative interpretation that smooth muscle rhythmicities are generated by a cardiac-like electrical pacemaker mechanism has not been substantiated in any smooth muscle preparation under normal physiological conditions. However, elements of this latter mechanism are likely to be present at least in some smooth muscles, serving to modulate pacemaking. 相似文献
962.
Zhaohui Pei Zhiqiang Zhuang Pingxi Xiao Jingzao Chen Hanfei Sang Jun Ren Zhenbiao Wu Guangmei Yan 《Cardiovascular toxicology》2009,9(2):70-77
This study was designed to examine the effect of infrasound exposure (5 Hz at 130 dB) on whole-cell L-type Ca2+ currents (WLCC) in rat ventricular myocytes and the underlying mechanism(s) involved. Thirty-two adult Sprague-Dawley rats
were randomly assigned to infrasound exposure and control groups. [Ca2+]i, WLCC, mRNA expression of the a1c subunit of L-type Ca2+ channels (LCC), and SERCA2 protein were examined on day 1, 7, and 14 after initiation of infrasound exposure. Fluo-3/AM fluorescence
and the laser scanning confocal microscope techniques were used to measure [Ca2+]i in freshly isolated ventricular myocytes. The Ca2+ fluorescence intensity (FI), denoting [Ca2+]i in cardiomyocytes, was significantly elevated in a time-dependent manner in the exposure groups. There was a significant
increase in WLCC in the 1-day group and a further significant increase in the 7- and 14-day groups. LCC mRNA expression measured
by RT-PCR revealed a significant rise in the 1-day group and a significant additional rise in the 7- and 14-day groups compared
with control group. SERCA2 expression was significantly upregulated in the 1-day group followed by an overt decrease in the
7- and 14-day groups. Prolonged exposure of infrasound altered WLCC in rat cardiomyocytes by shifting the steady-state inactivation
curves to the right (more depolarized direction) without altering the slope and biophysical properties of I
Ca,L. Taken together, our data suggest that changes in [Ca2+]I levels as well as expression of LCC and SERCA2 may contribute to the infrasound exposure-elicited cardiac response.
Zhaohui Pei and Zhiqiang Zhuang contributed equally to this work. 相似文献
963.
The whole-cell recording technique was used to investigate the actions of a calcium release channel ligand, ryanodine, on
calcium-activated chloride conductances, and to evaluate ryanodine-sensitive Ca2+-induced Ca2+ release from intracellular stores in cultured neonatal rat DRG neurones. The aim of the project was to use ryanodine as a
pharmacological tool to evaluate calcium-induced calcium release in the cell bodies of cultured DRG neurones. Action potential
after-depolarizations were attenuated by extracellular application of the chloride channel blocker, niflumic acid (10 μM),
and by ryanodine (10 μM); these actions occurred without concurrent changes in evoked action potentials. Ryanodine and caffeine
(10 mM) activated calcium-dependent conductances and the responses to ryanodine were attenuated by depletion of caffeine-sensitive
Ca2+ stores. The current clamp data were complicated by changes in potassium conductances so studies were carried out under voltage
clamp and voltage-activated calcium currents and calcium-activated chloride and non-selective cation currents were isolated
pharmacologically. Ryanodine (10 μM) evoked delayed, inward, calcium-activated non-selective cation and chloride currents
which reversed close to 0 mV and were attenuated by N-methyl-d-glucamine, niflumic acid and dantrolene. Consistent with actions on action potential after-depolarizations, niflumic
acid (10 μM) and ryanodine (10 μM) attenuated calcium-activated chloride currents evoked by calcium entry through voltage-activated
calcium channels. Niflumic acid and ryanodine had no effects on voltage-activated calcium currents evoked from a holding potential
of –90 mV by voltage step commands to 0 mV. In conclusion calcium-activated chloride conductances appear to be activated in
part by calcium released from ryanodine-sensitive stores, and significant calcium-induced calcium release may occur locally
in cell bodies of DRG neurones as a result of calcium entry through voltage-activated channels during an action potential.
Received: 6 July 1998 / Accepted: 30 November 1998 相似文献
964.
965.
Emerson M. Carmona Miguel Fernandez Juan J. Alvear-Arias Alan Neely H. Peter Larsson Osvaldo Alvarez Jose Antonio Garate Ramon Latorre Carlos Gonzalez 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(19)
The dissipation of acute acid loads by the voltage-gated proton channel (Hv1) relies on regulating the channel’s open probability by the voltage and the ΔpH across the membrane (ΔpH = pHex − pHin). Using monomeric Ciona-Hv1, we asked whether ΔpH-dependent gating is produced during the voltage sensor activation or permeation pathway opening. A leftward shift of the conductance-voltage (G-V) curve was produced at higher ΔpH values in the monomeric channel. Next, we measured the voltage sensor pH dependence in the absence of a functional permeation pathway by recording gating currents in the monomeric nonconducting D160N mutant. Increasing the ΔpH leftward shifted the gating charge-voltage (Q-V) curve, demonstrating that the ΔpH-dependent gating in Hv1 arises by modulating its voltage sensor. We fitted our data to a model that explicitly supposes the Hv1 voltage sensor free energy is a function of both the proton chemical and the electrical potential. The parameters obtained showed that around 60% of the free energy stored in the ΔpH is coupled to the Hv1 voltage sensor activation. Our results suggest that the molecular mechanism underlying the Hv1 ΔpH dependence is produced by protons, which alter the free-energy landscape around the voltage sensor domain. We propose that this alteration is produced by accessibility changes of the protons in the Hv1 voltage sensor during activation.The voltage-gated proton channel (Hv1) is gated by internal and external pH changes favoring proton extrusion during acute cytosolic acidosis, an essential function for cell physiology and pathophysiology (1). The wide diversity of cell types in which Hv1 is expressed, including different immune cells, sperm, microglia, lung epithelial cells, osteoclasts, cardiac cells, and cancer cells (1), renders this channel as a promising pharmacological target. A selective Hv1 modulation can be achieved by studying the molecular mechanisms of its distinctive pH dependence; although pH modulates other voltage-gated ion channels (2–5), the pH dependence of Hv1 is unique, since the channel opening depends only on the ΔpH (pHex − pHin) established across the membrane (6). Briefly, voltage-gated ion channels have a voltage-sensing domain (made up of transmembrane segments S1 to S4) coupled to a pore domain (S5 to S6) (7). Quite interestingly, Hv1 consists of only four transmembrane segments (from S1 to S4) flanked by intracellular N- and C-terminal domains (8, 9); thus, the permeation pathway, voltage sensor, and pH sensor(s) are contained in these four transmembrane segments. Moreover, the C-terminal domain folds into a coiled-coil structure between two Hv1 subunits to produce a dimer (10, 11), resulting in monomeric voltage-gated proton channels when the N- and C-terminal domains are deleted (10). Although the Hv1 monomer lacks the dimer cooperative opening (12, 13), it maintains its distinctive biophysical properties (10). However, although it has been reported that the monomeric Hv1 gating depends on pH, it is not clear whether the distinctive ΔpH-dependent gating is still present in this channel.The remarkable pH dependence of the Hv1 opening has been observed since the first proton current measurements (14, 15). However, its detailed analysis was only possible when fine precautions to control the pH during the proton current measurement were taken into account (6). These studies showed that conductance-voltage (G-V) curves and activation kinetics shift along the voltage axis as a function of the ΔpH regardless of the internal or external pH (6, 16). Although cloning of the Hv1 gene (8, 9) facilitated the search for mutations affecting the channel’s pH dependence (16–19), its molecular mechanism has remained elusive. In this regard, the Hv1 pH dependence has been challenging to understand, because it has mainly been studied by measuring the dimer’s proton current; in fact, the pH dependence of these currents could be produced by modulating the channel cooperativity, voltage sensor activation, or channel opening. Indeed, there is evidence indicating that pH affects both the voltage sensor movement (20, 21) and the channel’s unitary conductance (22). Consequently, the simultaneous processes that occur during Hv1 gating obscure the source of this ΔpH dependence. To overcome these difficulties, we used a nonconducting mutant of the Ciona intestinalis Hv1 (CiHv1) monomer to monitor the pH dependence exclusively on the voltage sensor activation. By measuring the voltage sensor movements directly from gating currents in the absence of cooperativity (10, 23) and proton currents (24–26), we asked whether the ΔpH-dependent gating in Hv1 originates during the voltage sensor activation or the permeation pathway opening. We found that the Hv1 voltage sensor movements are modulated by pH. In detail, the voltage sensor activation is coupled to the chemical free energy stored in the ΔpH, resulting in a ΔpH-dependent shift of the gating charge-voltage (Q-V) curves along the voltage axis. Accordingly, the Hv1 ΔpH-dependent gating is a consequence of the voltage sensor modulation. On the other hand, the gating currents kinetics depended on the internal and external pH values, indicating that the pH modulates the voltage sensor movements in a state-dependent manner. 相似文献
966.
967.