The Human Heart and Rat Brain IIA Na(+) Channels Interact with Different Molecular Regions of the β(1) Subunit

The α subunit of voltage-gated Na(+) channels of brain, skeletal muscle, and cardiomyocytes is functionally modulated by the accessory β(1), but not the β(2) subunit. In the present study, we used β(1)/β(2) chimeras to identify molecular regions within the β(1) subunit that are responsible for both the increase of the current density and the acceleration of recovery from inactivation of the human heart Na(+) channel (hH1). The channels were expressed in Xenopus oocytes. As a control, we coexpressed the β(1)/β(2) chimeras with rat brain IIA channels. In agreement with previous studies, the β(1) extracellular domain sufficed to modulate IIA channel function. In contrast to this, the extracellular domain of the β(1) subunit alone was ineffective to modulate hH1. Instead, the putative membrane anchor plus either the intracellular or the extracellular domain of the β(1) subunit was required. An exchange of the β(1) membrane anchor by the corresponding β(2) subunit region almost completely abolished the effects of the β(1) subunit on hH1, suggesting that the β(1) membrane anchor plays a crucial role for the modulation of the cardiac Na(+) channel isoform. It is concluded that the β(1) subunit modulates the cardiac and the neuronal channel isoforms by different molecular interactions: hH1 channels via the membrane anchor plus additional intracellular or extracellular regions, and IIA channels via the extracellular region only.