scholarly journals Modulation of the Cardiac Myocyte Action Potential by the Magnesium-Sensitive TRPM6 and TRPM7-like Current

2021 ◽  
Vol 22 (16) ◽  
pp. 8744
Author(s):  
Asfree Gwanyanya ◽  
Inga Andriulė ◽  
Bogdan M. Istrate ◽  
Farjana Easmin ◽  
Kanigula Mubagwa ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Action Potential ◽  
Voltage Clamp ◽  
Divalent Cation ◽  
Cardiac Myocyte ◽  
Cardiac Action Potential ◽  
Delayed Rectifier ◽  
Delayed Rectifier Current ◽  
Cardiac Action ◽  
In Cells

The cardiac Mg2+-sensitive, TRPM6, and TRPM7-like channels remain undefined, especially with the uncertainty regarding TRPM6 expression in cardiomyocytes. Additionally, their contribution to the cardiac action potential (AP) profile is unclear. Immunofluorescence assays showed the expression of the TRPM6 and TRPM7 proteins in isolated pig atrial and ventricular cardiomyocytes, of which the expression was modulated by incubation in extracellular divalent cation-free conditions. In patch clamp studies of cells dialyzed with solutions containing zero intracellular Mg2+ concentration ([Mg2+]i) to activate the Mg2+-sensitive channels, raising extracellular [Mg2+] ([Mg2+]o) from the 0.9-mM baseline to 7.2 mM prolonged the AP duration (APD). In contrast, no such effect was observed in cells dialyzed with physiological [Mg2+]i. Under voltage clamp, in cells dialyzed with zero [Mg2+]i, depolarizing ramps induced an outward-rectifying current, which was suppressed by raising [Mg2+]o and was absent in cells dialyzed with physiological [Mg2+]i. In cells dialyzed with physiological [Mg2+]i, raising [Mg2+]o decreased the L-type Ca2+ current and the total delayed-rectifier current but had no effect on the APD. These results suggest a co-expression of the TRPM6 and TRPM7 proteins in cardiomyocytes, which are therefore the molecular candidates for the native cardiac Mg2+-sensitive channels, and also suggest that the cardiac Mg2+-sensitive current shortens the APD, with potential implications in arrhythmogenesis.

scholarly journals Mechanical Load Effects on Cardiac Action Potential and Arrhythmogenic Ca2+Activitiesrevealed by a Novel Patch-Clamp-In-Gel Technology

2019 ◽  
Vol 116 (3) ◽  
pp. 97a
Author(s):  
Zhong Jian ◽  
Bence Hegyi ◽  
Mark Jaradeh ◽  
Zana A. Coulibaly ◽  
Yi-je Chen ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Action Potential ◽  
Mechanical Load ◽  
Cardiac Action Potential ◽  
Cardiac Action ◽  
Load Effects

SIMPLE EXPERIMENTS TO UNDERSTAND THE IONIC ORIGINS AND CHARACTERISTICS OF THE VENTRICULAR CARDIAC ACTION POTENTIAL

2002 ◽  
Vol 26 (3) ◽  
pp. 185-194 ◽  
Author(s):  
Jean-Yves Le Guennec ◽  
Christophe Vandier ◽  
Gilles Bedfer
Keyword(s):  
Action Potential ◽  
Electrical Activity ◽  
Voltage Clamp ◽  
Undergraduate Students ◽  
Papillary Muscle ◽  
Action Potentials ◽  
Heart Function ◽  
Cardiac Action Potential ◽  
Extracellular Potassium ◽  
Cardiac Action

Electrophysiological experiments are helpful for students to understand the role of electrical activity in heart function. Papillary muscle, which belongs to the ventricle, offers the advantage of being easily studied using glass microelectrodes. In addition, there is commercially available software that simulates ventricular electrical activity and can help overcome some difficulties, such as voltage clamp experiments, which need expensive apparatus when used for studies on living preparations. Here, we present a class practical session that is taken by undergraduate students at our University. In the first part of this class, students record action potentials from papillary muscles with the use of glass microelectrodes, and they change extracellular conditions to study the ionic basis of the action potential. In the second part of the class, students simulate action potentials using the Oxsoft Heart model (v. 4.0) and model their previous experiments on papillary muscle to quantify the effects. In particular, the model is very helpful in promoting understanding of the effect that extracellular potassium has on cardiac action potential by simulating voltage clamp experiments. This twin approach of papillary muscle experiments and computer modeling leads to a good understanding of the functioning of the action potential and can help introduce discussion of some abnormal cardiac functioning.

Thermal adaptation of the crucian carp (Carassius carassius) cardiac delayed rectifier current, IKs, by homomeric assembly of Kv7.1 subunits without MinK

2011 ◽  
Vol 301 (1) ◽  
pp. R255-R265 ◽  
Author(s):  
Minna Hassinen ◽  
Salla Laulaja ◽  
Vesa Paajanen ◽  
Jaakko Haverinen ◽  
Matti Vornanen
Keyword(s):  
Action Potential ◽  
Crucian Carp ◽  
Thermal Adaptation ◽  
Cardiac Action Potential ◽  
Delayed Rectifier ◽  
Carassius Carassius ◽  
Electrical Stability ◽  
Activation Kinetics ◽  
Cardiac Action ◽  
Wide Range

Ectothermic vertebrates experience acute and chronic temperature changes which affect cardiac excitability and may threaten electrical stability of the heart. Nevertheless, ectothermic hearts function over wide range of temperatures without cardiac arrhythmias, probably due to special molecular adaptations. We examine function and molecular basis of the slow delayed rectifier K+ current ( IKs) in cardiac myocytes of a eurythermic fish ( Carassius carassius L.). IKs is an important repolarizing current that prevents excessive prolongation of cardiac action potential, but it is extremely slowly activating when expressed in typical molecular composition of the endothermic animals. Comparison of the IKs of the crucian carp atrial myocytes with the currents produced by homomeric Kv7.1 and heteromeric Kv7.1/MinK channels in Chinese hamster ovary cells indicates that activation kinetics and pharmacological properties of the IKs are similar to those of the homomeric Kv7.1 channels. Consistently with electrophysiological properties and homomeric Kv7.1 channel composition, atrial transcript expression of the MinK subunit is only 1.6–1.9% of the expression level of the Kv7.1 subunit. Since activation kinetics of the homomeric Kv7.1 channels is much faster than activation of the heteromeric Kv7.1/MinK channels, the homomeric Kv7.1 composition of the crucian carp cardiac IKs is thermally adaptive: the slow delayed rectifier channels can open despite low body temperatures and curtail the duration of cardiac action potential in ectothermic crucian carp. We suggest that the homomeric Kv7.1 channel assembly is an evolutionary thermal adaptation of ectothermic hearts and the heteromeric Kv7.1/MinK channels evolved later to adapt IKs to high body temperature of endotherms.

scholarly journals Four ways to fit an ion channel model

2019 ◽  
Author(s):  
M. Clerx ◽  
K.A. Beattie ◽  
D.J. Gavaghan ◽  
G.R. Mirams
Keyword(s):  
Action Potential ◽  
Ion Channel ◽  
Voltage Clamp ◽  
Time Constant ◽  
Cardiac Action Potential ◽  
Channel Kinetics ◽  
Safety Critical ◽  
Independent Validation ◽  
Cardiac Action ◽  
Ion Channel Kinetics

ABSTRACTComputational models of the cardiac action potential are increasingly being used to investigate the effects of genetic mutations, predict pro-arrhythmic risk in drug development, and to guide clinical interventions. These safety-critical applications, and indeed our understanding of the cardiac action potential, depend on accurate characterisation of the underlying ionic currents. Four different methods can be found in the literature to fit ionic current models to single-cell measurements: (Method 1) fitting model equations directly to time constant, steady-state, and I-V summary curves; (Method 2) fitting by comparing simulated versions of these summary curves to their experimental counterparts; (Method 3) fitting to the current traces themselves from a range of protocols; and (Method 4) fitting to a single current trace from an information-rich voltage clamp protocol. We compare these methods using a set of experiments in which hERG1a current from single Chinese Hamster Ovary (CHO) cells was characterised using multiple fitting protocols and an independent validation protocol. We show that Methods 3 and 4 provide the best predictions on the independent validation set, and that the short information-rich protocols of Method 4 can replace much longer conventional protocols without loss of predictive ability. While data for Method 2 is most readily available from the literature, we find it performs poorly compared to Methods 3 and 4 both in accuracy of predictions and computational efficiency. Our results demonstrate how novel experimental and computational approaches can improve the quality of model predictions in safety-critical applications.Statement of SignificanceMathematical models have been constructed to capture and share our understanding of the kinetics of ion channel currents for almost 70 years, and hundreds of models have been developed, using a variety of techniques. We compare how well four of the main methods fit data, how reliable and efficient the process of fitting is, and how predictive the resulting models are for physiological situations. The most widely-used traditional approaches based on current-voltage and time constant-voltage curves do not produce the most predictive models. Short, optimised experimental voltage clamp protocols can be used to create models that are as predictive as ones derived from traditional protocols, opening up possibilities for measuring ion channel kinetics faster, more accurately and in single cells. As these models often form part of larger multi-scale action potential and tissue electrophysiology models, improved ion channel kinetics models could influence the findings of thousands of simulation studies.

Biphasic Effects of Isoflurane on the Cardiac Action Potential

2002 ◽  
Vol 97 (5) ◽  
pp. 1209-1217 ◽  
Author(s):  
Akihiro Suzuki ◽  
Kei Aizawa ◽  
Susanne Gassmayr ◽  
Zeljko J. Bosnjak ◽  
Wai-Meng Kwok
Keyword(s):  
Action Potential ◽  
Cardiac Electrophysiology ◽  
Ionic Currents ◽  
Cardiac Action Potential ◽  
Delayed Rectifier ◽  
Inactivation Kinetics ◽  
Inhibitory Effects ◽  
Patch Clamp Technique ◽  
Cardiac Action ◽  
Chord Conductance

Background The mechanism underlying isoflurane modulation of cardiac electrophysiology is not well understood. In the present study, the authors investigated the effects of isoflurane on the cardiac action potential (AP) characteristics. The results were correlated to modulation of the L-type calcium (I(Ca,L)), the delayed-rectifier potassium (I(Kdr)), and the inward-rectifier potassium (I(Kir)) currents. Methods Single ventricular myocytes were enzymatically isolated from guinea pig hearts. The current clamp and whole cell voltage clamp configurations of the patch clamp technique were used to monitor the cardiac AP and ionic currents, respectively. A dynamic AP voltage protocol that mimicked changes in membrane potential during an AP was used to monitor the I(Ca,L), I(Kdr) and I(Kir). Results Isoflurane produced a concentration-dependent, biphasic effect on the AP duration (APD). At 0.6 mm (1.26 vol%), isoflurane significantly increased APD50 and APD90 by 50.0 +/- 7.6% and 48.9 +/- 7.2%, respectively (P < 0.05; n = 6). At 1.0 mm (2.09 vol%), isoflurane had no significant effect on APD (n = 6). In contrast, at 1.8 mm (3.77 vol%), isoflurane decreased APD50 and APD90 by 38.3 +/- 5.4% and 32.2 +/- 5.5%, respectively (P < 0.05; n = 7). The inhibitory effects of isoflurane on I(Kdr) chord conductance were greater than those on I(Ca,L) (P < 0.05; n = 6/group). Both I(Ca,L) inactivation and I(Kdr) activation kinetics were accelerated by isoflurane. Isoflurane had no significant effects on I(Kir) chord conductance (n = 6). Conclusion At the lower anesthetic concentration, the prolongation of the APD may be the result of the dominant inhibitory effects of isoflurane on I(Kdr). At the higher concentration, the shortening of the APD may be caused by the inhibitory effects on I (Ca,L) combined with the isoflurane-induced acceleration of I(Ca,L) inactivation kinetics. Because I(Kdr) is significantly inhibited by isoflurane, I(Kir) appears to be the major repolarizing current, which is minimally affected by isoflurane.

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