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Joined 2026-09-21 Message
Incoming links: Myotonia congenita
An ion channel can disturb cellular electrical activity by changing unitary electrical conductance, open probability, gating kinetics or the number delivered to the cell membrane. A useful organizing relation isHere outward electric current is positive. Altering one channel's biophysical behavior changes the balance governing membrane potential and hence the timing or recurrence of action potentials.
Long QT syndrome, type 3. Certain disease-associated SCN5A variants impair fast ion-channel inactivation of the cardiac voltage-gated sodium channel NaV1.5. Instead of vanishing promptly after the upstroke, a small persistent inward sodium electric current remains during the plateau and repolarization. Because in this phase, the residual electric current is inward and opposes the outward electric currents that would terminate the cardiac action potential. The ventricular action potential lasts longer, extending the QT interval on the electrocardiogram. Excessively prolonged or uneven repolarization permits early afterdepolarizations and dangerous ventricular rhythm disturbances.
Genetic association identifies the channel, while voltage clamp distinguishes defective ion-channel inactivation from a mere increase in channel abundance. Recordings of disease-associated channels show persistent or bursting openings; coupling measured mutant sodium electric current into an otherwise modeled cardiac membrane through dynamic clamp tests whether that kinetic defect prolongs the action potential. The phenotype is variant-specific: not every SCN5A variant increases late electric current or causes long QT syndrome.[ref]
Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia by Qing Wang and others. Human Molecular Genetics 4, pp. 1603–1607: familial variants affecting the inactivation machinery
[ref]Long-QT syndrome-related sodium channel mutations probed by the dynamic action potential clamp technique by Géza Berecki and others. Measured mutant-channel currents coupled to a ventricular-cell model test action-potential prolongation
Myotonia congenita. CLCN1 encodes the skeletal-muscle ClC-1 chloride channel, which normally supplies a large resting stabilizing electrical conductance. Because the chloride reversal potential is near the resting membrane potential, that pathway resists small depolarizing disturbances. Loss of functional channels, reduced electrical conductance, or a shift in opening toward more positive membrane potential reduces the resting electrical shunt. Potassium accumulation in the transverse-tubule space during activity can then produce larger depolarizing afterpotentials and trigger further muscle action potentials after the intended stimulus has ceased. Continued electrical firing sustains contraction and delays relaxation: this is myotonia, rather than a primary inability of the contractile apparatus to relax.
Patient-family linkage and variant analysis connect the disease to ClC-1. Functional recordings of disease-associated channels demonstrate shifted voltage dependence and reduced availability near resting membrane potential; single-channel and noise measurements also resolve two conductive protopores and their gating behavior. Different variants can act through different mechanisms, so a gating shift is an example rather than an explanation of every case.[ref]
The skeletal muscle chloride channel in dominant and recessive human myotonia by Manuela C. Koch and others. Science 257, pp. 797–800: familial disease linked to the muscle chloride-channel gene
[ref]Mutations in dominant human myotonia congenita drastically alter the voltage dependence of the ClC-1 chloride channel by Michael Pusch and others. Neuron 15, pp. 1455–1463: disease-associated changes in voltage dependence
[ref]The muscle chloride channel ClC-1 has a double-barreled appearance that is differentially affected in dominant and recessive myotonia by Caterina Saviane and others. Single-channel and fluctuation analysis of ClC-1 and myotonia-associated gating changes
These examples connect contrasting current defects to their consequences: persistent inward sodium electric current prolongs cardiac action potentials, whereas loss of stabilizing resting chloride electrical conductance permits repetitive skeletal-muscle action potentials. Both causal chains require functional channel measurements in addition to a disease-associated sequence change.