Myocardial ischemia\infarction and heart failure are among the leading causes of morbidity and mortality worldwide. Activation of ERK signaling has been shown to promote cardioprotection from Ischemia-Reperfusion (I/R) Injury. ZnT-1, was found to interact with Raf-1 kinase, leading to downstream activation of ERK. In addition, we previously demonstrated that ZnT-1 inhibits L type calcium channels (LTCC) through interaction with the beta-subunit of the voltage-gated calcium channels. Here, we explored further the roles of ZnT-1 in the heart. Specifically, we studied the ability of ZnT-1 to protect cardiomyocytes from I/R injury. In addition, we explored the effect of ZnT-1 on T-type calcium channels (TTCC), which may have important role in the development of hypertrophy and automaticity in the diseased myocardium. In contrast to its inhibition of the LTCC, ZnT-1 stimulated TTCC currents and increased the surface expression of CaV3.1 (458 ±86 % of control, p<0.005). Inactive Raf-1 abolished ZnT-1 augmentation of the TTCC currents. In a model of I/R injury in HL-1 cells ZnT-1 increased Phospho-ERK and markedly reduced lactate dehydrogenase (LDH) release and activated caspase (programmed cell death marker). Conversely, knockdown of endogenous ZnT-1 by shRNA inhibited ERK phosphorylation and markedly increased LDH release following I/R. The MEK inhibitor PD98059 completely abolished the protective effect of ZnT-1. A truncated form of ZnT-1 lacking the C-terminal domain failed to induce ERK activation and did not protect the cells from I/R injury. In contrast, the C-terminal domain was sufficient to induce ERK activation and I/R protection. CONCLUSION: ZnT-1 stimulates the activity of the TTCC in a process involving ERK activation and increased TTCC surface expression. In addition to this role as a regulator of calcium homeostasis, ZnT-1 confers protection from I/R injury through its ability to activate ERK signaling. Thus, ZnT-1 seems to have important roles as a regulator of cardiac function.