The dihydropyridine receptors (DHPR) are L-type voltage-gated calcium channels that regulate the flux of calcium ions across the cell membrane. Here we present the three-dimensional (3D) structure at similar to27 Angstrom resolution of purified skeletal muscle DHPR, as determined by electron microscopy and single particle analysis. Here both biochemical and 3D structural data indicate that DHPR is dimeric. DHPR dimers are composed of two arch-shaped monomers similar to210 Angstrom across and similar to75 Angstrom thick, that interact very tightly at each end of the arch. The roughly toroidal structure of the two monomers encloses a cylindrical space of similar to80 Angstrom diameter, which is then closed on each side by two dome-shaped protein densities reaching over from each monomer arch. The dome-shaped domains have a length of similar to80-90 Angstrom and a maximum height of similar to45 Angstrom. Small orifices punctuate their exterior surface. The 3D structure disclosed here may have important implications for the understanding of DHPR Ca2+ channel function. We also propose a model for its in vivo interactions with the calcium release channel at the junctional sarcoplasmic recticulum. (C) 2002 Elsevier Science Ltd. All rights reserved.