Aberrant Deactivation-Induced Gain of Function in TRPM4 Mutant Is Associated with Human Cardiac Conduction Block

Cell Reports
Wenying XianPeter Lipp

Abstract

A gain-of-function mutation in the Ca2+-activated transient receptor potential melastatin member 4 (TRPM4A432T) is linked to life-threatening cardiac conduction disturbance, but the underlying mechanism is unclear. For deeper insights, we used photolysis of caged Ca2+, quantitative Ca2+, and electrophysiological measurements. TRPM4A432T's 2-fold larger membrane current was associated with 50% decreased plasma membrane expression. Kinetic analysis unveiled 4-fold slower deactivation that was responsible for the augmented membrane current progressively rising during repetitive human cardiac action potentials. Rational mutagenesis of TRPM4 at position 432 revealed that the bulkiness of the amino acid was key to TRPM4A432T's aberrant gating. Charged amino acids rendered the channel non-functional. The slow deactivation caused by an amino acid substitution at position 432 from alanine to the bulkier threonine represents a key contributor to the gain of function in TRPM4A432T. Thus, our results add a mechanism in the etiology of TRP channel-linked human cardiac channelopathies.

Citations

Jan 22, 2019·Nature Reviews. Cardiology·Thomas HofRomain Guinamard
Jul 19, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Wenying XianPeter Lipp
Feb 11, 2021·Biomolecules·Anna BorgströmPaulina Stokłosa
Jan 1, 2021·Cardiovascular Therapeutics·Mohamed-Yassine Amarouch, Jaouad El Hilaly

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