The Human Heart and Rat Brain IIA Na⁺ Channels Interact with Different Molecular Regions of the β₁ Subunit

The α subunit of voltage-gated Na⁺ channels of brain, skeletal muscle, and cardiomyocytes is functionally modulated by the accessory β₁, but not the β₂ subunit. In the present study, we used β₁/β₂ chimeras to identify molecular regions within the β₁ 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 β₁/β₂ chimeras with rat brain IIA channels. In agreement with previous studies, the β₁ extracellular domain sufficed to modulate IIA channel function. In contrast to this, the extracellular domain of the β₁ subunit alone was ineffective to modulate hH1. Instead, the putative membrane anchor plus either the intracellular or the extracellular domain of the β₁ subunit was required. An exchange of the β₁ membrane anchor by the corresponding β₂ subunit region almost completely abolished the effects of the β₁ subunit on hH1, suggesting that the β₁ membrane anchor plays a crucial role for the modulation of the cardiac Na⁺ channel isoform. It is concluded that the β₁ 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.