TRPA1 ion channel stimulation enhances cardiomyocyte contractile function via a CaMKII-dependent pathway.

TRPA1 ion channel stimulation enhances cardiomyocyte contractile function via a CaMKII-dependent pathway.

Andrei Spencer R; Ghosh Monica; Sinharoy Pritam; Dey Souvik; Bratz Ian N; Damron Derek S

Channels (Austin, Tex.)

2017

2017-11

RATIONALE: Transient receptor potential channels of the ankyrin subtype-1 (TRPA1) are non-selective cation channels that show high permeability to calcium. Previous studies from our laboratory have demonstrated that TRPA1 ion channels are expressed in adult mouse ventricular cardiomyocytes (CMs) and are localized at the z-disk, costamere and intercalated disk. The functional significance of TRPA1 ion channels in the modulation of CM contractile function have not been explored. OBJECTIVE: To identify the extent to which TRPA1 ion channels are involved in modulating CM contractile function and elucidate the cellular mechanism of action. METHODS AND RESULTS: Freshly isolated CMs were obtained from murine heart and loaded with Fura-2 AM. Simultaneous measurement of intracellular free Ca(2+) concentration ([Ca(2+)]i) and contractility was performed in individual CMs paced at 0.3 Hz. Our findings demonstrate that TRPA1 stimulation with AITC results in a dose-dependent increase in peak [Ca(2+)]i and a concomitant increase in CM fractional shortening. Further analysis revealed a dose-dependent acceleration in time to peak [Ca(2+)]i and velocity of shortening as well as an acceleration in [Ca(2+)]i decay and velocity of relengthening. These effects of TRPA1 stimulation were not observed in CMs pre-treated with the TRPA1 antagonist, HC-030031 (10 micromol/L) nor in CMs obtained from TRPA1(-/-) mice. Moreover, we observed no significant increase in cAMP levels or PKA activity in response to TRPA1 stimulation and the PKA inhibitor peptide (PKI

[Ca2+]i; *Myocardial Contraction; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism; CaMKII; Cardiac/*metabolism; cardiomyocytes; contractility; Inbred C57BL; Knockout; Mice; Myocytes; TRPA1; TRPA1 Cation Channel/deficiency/*metabolism

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587–603

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