Abstract
BACKGROUND : Recent findings indicate that the membranous protein ZnT-1 acts as an inhibitor of L-type calcium channels (LTCC). However, no direct interaction between ZnT-1 and the LTCC α 1 C subunit was demonstrated. Recently, we found that atrial tachypacing in rats augments the expression of ZnT-1 in conjunction with AERP reduction. Therefore, we postulated that ZnT-1 may play a role in atrial tachycardia remodeling of patients with AF. In this study, we assessed the atrial expression of ZnT-1 in humans with AF or sinus rhythm (SR). In addition, in order to explore the mechanism of action of ZnT-1 we used heterologous expression system, and tested the possibility that ZnT-1 interacts with the β-subunit of the LTCC. METHODS AND RESULTS : From 39 patients (27 in SR and 12 in AF) undergoing open heart surgery, we collected right atrial appendage tissue. The expression of ZnT-1 was analyzed. β-actin served as an internal loading control and data was compared to a rat standard (STD). Overall, AF patients (n = 12) had median ZnT-1/β-actin of 1.80 STD (inter-quartile range 1.26 to 2.85) vs. 0.73 STD (0.24 to 1.64) in the SR group (p = 0.002). Multivariate analysis determined that AF and increased BMI are the only independent variables associated with higher levels of ZnT-1. In Xenopus oocytes, the absence of the β-subunit prevented the inhibition of LTCC activity by ZnT-1 (127 ± 43nA and 153 ± 39nA for control and ZnT-1 containing oocytes, respectively, p>0.5, n = 8). In addition, ZnT-1 failed to inhibit the current when the α-subunit was truncated in the part essential for the interaction with the β subunit (2037 ± 300nA and 1938 ± 341nA for control and ZnT-1 containing oocytes, respectively, p>0.5, n = 3). Direct interaction between ZnT-1 and the LTCC β-subunit was demonstrated by co-immunoprecipitation of ZnT-1-myc and the β-subunit, using anti-myc antibodies (n = 3) CONCLUSIONS : This work provides first evidence for an increased ZnT-1 expression in patients with AF and marks it as a putative missing link in the development of atrial electrical remodeling. An interaction of the LTCC β-subunit and the ZnT-1 plays a role in the molecular mechanism by which ZnT-1 inhibits the LTCC.
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