Novel Mechanism for Suppression of Hyperpolarization-activated Cyclic Nucleotide-gated Pacemaker Channels by Receptor-like Tyrosine Phosphatase-α

We have previously reported an important role of increased tyrosine phosphorylation activity by Src in the modulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Here we provide evidence showing a novel mechanism of decreased tyrosine phosphorylation on HCN channel properties. We found that the receptor-like protein-tyrosine phosphatase-alpha (RPTP alpha) significantly inhibited or eliminated HCN2 channel expression in HEK293 cells. Biochemical evidence showed that the surface expression of HCN2 was remarkably reduced by RPTP alpha, which was in parallel to the decreased tyrosine phosphorylation of the channel protein. Confocal imaging confirmed that the membrane surface distribution of the HCN2 channel was inhibited by RPTP alpha. Moreover, we detected the presence of RPTP alpha proteins in cardiac ventricles with expression levels changed during development. Inhibition of tyrosine phosphatase activity by phenylarsine oxide or sodium orthovanadate shifted ventricular hyperpolarization-activated current (I-f, generated by HCN channels) activation from nonphysiological voltages into physiological voltages associated with accelerated activation kinetics. In conclusion, we showed a critical role RPTP alpha plays in HCN channel function via tyrosine dephosphorylation. These findings are also important to neurons where HCN and RPTP alpha are richly expressed.