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

Wenying Xian, Xin Hui, Qinghai Tian, Hongmei Wang, Alessandra Moretti, Karl Ludwig Laugwitz, Veit Flockerzi, Sandra Ruppenthal, Peter Lipp

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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. A mutation in TRPM4 (A432T) is linked to life-threatening cardiac conduction disturbances in patients. Using a combination of biophysical techniques, Xian et al. demonstrate that calcium-dependent deactivation between heartbeats is aberrant and highlights the etiology of human cardiac channelopathies. These findings offer putative new pharmacological targets for disease management in human patients.

Original languageEnglish
Pages (from-to)724-731
Number of pages8
JournalCell Reports
Volume24
Issue number3
DOIs
StatePublished - 17 Jul 2018
Externally publishedYes

Keywords

  • TRPM4
  • calcium
  • cardiac arrhythmia
  • disease mechanism
  • flash photolysis
  • inherited human disease
  • membrane current
  • molecular modeling
  • mutation
  • patch clamp

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