The cytoplasmic halves of the pore-lining helices in voltage-gated sodium and calcium channels contain exceptionally conserved asparagine residues in each of the four repeat domains. The exceptional conservation implies important roles of the asparagines, which are unknown. Previous studies demonstrated that mutations of the asparagines affect activation and slow inactivation of the channels, as well as action of pore-binding drugs, including local anaesthetics and mibefradil. In the absence of open-channel structures, underlying mechanisms are unclear. Here we modeled the open, closed, and inactivated conformations of Cav1.2 and Nav1.5 channels using available x-ray structures of potassium and sodium channels as templates. The energy of each channel state was optimized by the Monte Carlo-minimization protocol. The asparagines do not face the pore lumen in any of the modeled states. In the closed channel models, the asparagines occur in hydrophobic environments that would bring a destabilizing contribution to the closed state energy. In the open-channel models, the asparagine residue in each domain forms an interdomain H-bond with a polar residue, which is typically nine positions downstream from the conserved asparagine in the preceding domain. The H-bonds are stabilized by surrounding hydrophobic residues. We propose that mutations of the asparagines affect activation-inactivation of the channels and drug action through destabilizing the open state. Diversity of H-bonding partners explains different effects of mutations of individual asparagines on the channel activation, inactivation, and drug sensitivity. Supported by NSERC grant to BSZ, the RAS program “Molecular and Cell Biology” to DBT, and CIHR award to IB.