Vertebrates use two different systems for controlling muscle contraction, with DHPR calcium channels acting as voltage sensors in both. In skeletal muscle, tetrads of DHPR proteins associate directly with ryanodine receptors (RyRs). In response to electrical stimulation, DHPRs directly signal RyRs, causing release of internal stores of calcium and muscle contraction. By contrast, DHPR and RyR in cardiac muscle are located near one another in adjoining membranes but do not interact directly. For DHPR to activate RyR, the channel must allow a flood of extracellular calcium into the cell. All invertebrate muscles use this latter system.
Using structural analysis of muscle samples from four species that characterize the vertebrate–invertebrate evolutionary junction, the authors found a correlation between lying on the vertebrate side of the evolutionary tree and having an organized DHPR–RyR structure.Although the functional difference between the systems is metabolically important, it can be reversed with some simple genetics. Previous work showed that substitution of either DHPR or RyR skeletal proteins with the cardiac isoform causes a shift toward the cardiac structure and function in tissue culture cells.