Crosstalk between L-type calcium channels and ZnT-1, a new player in rate-dependent cardiac electrical remodeling.
Crosstalk between two membrane transport systems is an established mechanism underlying regulation. In this study, we investigated the interaction between ZnT-1, a putative plasma membrane zinc transporter, and L-type voltage-dependent calcium channels (LTCC). In the atrium of the myocardium decreased activity of the LTCC is a dominant feature of patients with atrial fibrillation. The trigger for this inhibition has been attributed to the rapid firing rates and consequent calcium overload in the atrial cardiomyocytes. However, the underlying mechanism of LTCC inhibition is still to be elucidated. Here, we showed that the expression of ZnT-1 inhibits the activity of L-type channels during electrical remodeling induced by rapid pacing. (i) Direct manipulations of ZnT-1 expression in cultured cardiomyocytes either by ZnT-1 overexpression or by ZnT-1 silencing with siRNA, decreased or enhanced, respectively, the barium influx through the LTCC. (ii) Co-expression of ZnT-1 with LTCC in Xenopus oocytes decreased whole cell barium current through LTCC. (iii) Rapid pacing of cultured cardiomyocytes (4 h, 100 ms cycle) increased ZnT-1 protein expression and inhibited the voltage-dependent divalent cation influx through the LTCC. Moreover, silencing ZnT-1 with siRNA prevented the rapid pacing induced inhibition of the LTCC (iv) Atrial pacing of anesthetized adult rats (4 h, 50 ms cycle) led to a significant increase in atrial ZnT-1 protein expression in parallel with the typical decrease of the refractory period in the atria. Taken together, these findings demonstrate that crosstalk between ZnT-1 and the L-type calcium channels may underlie atrial response to rapid pacing, suggesting that ZnT-1 is a significant participant in rate-dependent cardiac electrical remodeling.
Beharier
Ofer
O
Department of Physiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Etzion
Yoram
Y
Katz
Amos
A
Friedman
Hani
H
Tenbosh
Nir
N
Zacharish
Saar
S
Bereza
Sergiy
S
Goshen
Uri
U
Moran
Arie
A
D000818:Animals; D001464:Barium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000502:physiology*; D027682:Cation Transport Proteins; D002478:Cells, Cultured; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling / Q000502:physiology*; D014982:Xenopus laevis
D020746:Calcium Channels, L-Type; D027682:Cation Transport Proteins; D008565:Membrane Proteins; C092392:Slc30a1 protein, rat; D001464:Barium