PORPHYRIN INDUCED CA2+ RELEASE FROM SR

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Porphyrins are prosthetic groups for a large number of biological molecules which carry out diverse roles in nature. When coordinated to a central metal ion, porphyrins perform such functions as oxygen transport and storage (myoglobin and hemoglobin), electron and energy transfer (cytochromes and chlorophylls), and biocatalysis (coenzyme B12, cytochrome P-450). We have recently shown that low concentration of the porphyrin, meso-Tetra(4-N-methylpyridyl) porphine tetraiodide is a very potent stimulator of Ca2+ release from skeletal muscle sarcoplasmic reticulum (SR) vesicles. Experiments carried out using known inhibitors and stimulators of the Ca2+ release channel from sarcoplasmic reticulum indicate that this porphyrin is interacting with the Ca2+ release system from the SR. The main objective of this proposal are: (1) by testing various related porphyrins, determine whether of not there is a correlation between the effectiveness of stimulating Ca2+ release and the redox potential of the porphyrin. If a good correlation exists, (2) to estimate the redox potential of the receptor site at which the porphyrin interacts. (3) to determine directly how various porphyrins effect the gating characteristics of the Ca2+ release channel (a) following fusion of SR vesicles to an artificial membrane and (b) following incorporation of the isolated Ca2+ release protein from skeletal muscle sarcoplasmic reticulum. (4) To determine whether of not the " foot structure " which connects the T- tubule and the terminal end of the SR contains an endogenous porphyrin which is coupled t other Ca2+ release machinery via a redox reaction. In spite of recent advances in identifying a protein component involved in the Ca2+ release machinery, the molecular mechanism underlying excitation- contraction coupling remains unknown. As a result of this project, the interaction between porphyrins and the E-C coupling machinery in skeletal muscle will be described. If, as previously proposed, sulfhydryl oxidation and reduction is a key step in E-C coupling, this study should yield critical information regarding the gating and molecular interaction underlying this key step in skeletal muscle contraction.