Journal
CELL REPORTS
Volume 24, Issue 3, Pages 724-731Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.06.034
Keywords
-
Categories
Funding
- Deutsche Forschungsgemeinschaft [DFG] [TRR SFB 152]
- medical faculty (HOMFORexcellent)
- Alexander von Humboldt research scholarship in the Flockerzi lab
Ask authors/readers for more resources
A gain-of-function mutation in the Ca2+-activated transient receptor potential melastatin member 4 (TRPM4(A432T)) 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. TRPM4(A432T)'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 TRPM4(A432T)'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 TRPM4(A432T). Thus, our results add a mechanism in the etiology of TRP channel-linked human cardiac channelopathies.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available