Functions of the two types of calcium release channels in the sarcoplasmic reticulum of skeletal muscle.

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In the sarcoplasmic reticulum (SR) of frog skeletal muscle, two types of ryanodine receptors (calcium release channels) , corresponding to mammalian type 1 and type 3, respectively, are expressed in about equal amount. This study is aiming at elucidation of the physiological role of each of these two types of channels. We have obtained the following results. (1) The properties of type 3 channels were examined by using skeletal muscles of type 1-knockout mice that expresses only type 3 channels, and found to show Ca-induced Ca release (CICR) activity but require a higher Ca concentration for activation. (2) We made type 3-knockout mice, the skeletal mucle of which showed normal EC coupling. (3) only type 1 channel but neither type 2 nor type 3 channels can rescue impaired EC coupling in skeletal muscle of type 1-knockout mice. (4)We have been able to make mutant mice in which both type 1 and type 3 channels are knocked out. The SR of skeletal muscle of these mice can accumulate Ca but CICR is absent, indicating that in mouse skeletal muscle the expressed Ca release channels are only types 1 and 3, but not type 2. It was also found that "depolarization" -induced Ca release is the property of type 1 channels. (5) Calmodulin was found to enhance CICR at low activating concentration of Ca in addition to inhibition of CICR so far reported that is shown at higher activating concentrations of Ca. It shows mainly an enhancing effect on type 1 channels and an inhibitory effect on type 3 channels. (6) Ryanodine, which does not bind to closed channels, binds to channels open by physiological stimulation and fixes in an open state to cause contracture, in addition to the wellknown fact that it binds channels open by Ca (open in CICR mode). Therefore, it will be possible by using radioactive ryanodine, to determine the relative magnitude of opening of type 1 and 3 channel in physiological contraction.