| Biosystems are recently found to adopt a smart strategy to achieve the complex functions in signal transduction through the clustering and cooperation of homogeneous molecules. In both eukaryotic and prokaryotic cells, membrane receptors are often found to form two-dimensional arrays. These arrayed receptors structurally and functionally interact with each other and enable the receptor array act as a unitary molecular biosystem for signal transduction and processing. Recently, it is found that these receptor arrays play pivotal roles in many signaling events, for instance bacterial chemotaxis, T/B cell activation, etc. These receptor arrays show super-high sensitivity, specificity and gain in signal transduction, which are much better than the current artificial signal processing systems.Ryanodine receptors (RyRs)/calcium release channels usually form two-dimensional array in the membrane of sarcoplasmic reticulum (SR) in muscle cells. In the recent years, more and more direct or indirect evidence suggest that the coupling between neighboring RyRs seems playing an important role in shaping the dynamics of SR calcium release. However, the physiological roles of array-based behavior of RyRs and even the working mechanism of RyR array are still unclear, which largely limit the further understanding of muscle"excitation-contraction"coupling (e-c coupling). With the purpose to solve this problem, we combined computer simulation and biophysical assays to study working mechanism of RyR array and its detailed function in this dissertation.Based on the previous finding that the inter-RyRs coupling would decrease along with the activation of RyRs, we proposed a novel working mechanism to describe the operation of RyR array, which is called"dynamic coupling". We found that the strong inter-RyRs coupling in the resting state could increase the system stability in resting condition and enhance the response efficiency of the array to the input signal, the combination of which could greatly optimize the signal-to-noise ratio of system in signal transduction. On the other hand, we also found that the timely reduction of the coupling between opening RyRs would facilitate the rapid termination of RyR array, which would fulfill the requirement of the rapid Ca2+ recycling in e-c coupling. With"dynamic coupling"model, we successfully solved the intrinsic paradox between the inter-RyRs coupling and rapid termination of Ca2+ release, which was ever thought as a big doubt to the physiological sense of inter-RyRs coupling. Therefore, the"dynamic coupling"model further established the importance of inter-RyRs coupling in e-c coupling.Moreover, we further found the association between the abrogated inter-RyRs coupling and the malignant hyperthermia (MH, a lethal muscle disease) by combining biophysical techniques and computer simulations. It is actually the first time to report the direct relationship between the defected coupling between arrayed receptors and a disease. We purified the mutant RyRs (R615C) from the skeletal muscle of pig animal model with MH. Surprisingly, we found that there was obvious reduction of interaction between MH RyRs, relative to wild type (WT) RyRs. If the reduced coupling between RyRs was introduced into"dynamic coupling"model, we could successfully simulate the MH characteristic syndrome, including the leaky Ca2+ release and sustained RyR channel opening following exposure to halothane. According to this finding, we proposed a novel mechanism for MH based on the defected inter-RyRs coupling, providing a new angle for the further consideration of MH pathophysiology. Meanwhile, this finding also suggests that the defects in the inter-receptor cooperation could be a new source of disease, which further shows the importance of inter-receptor coupling in regular array in signal transduction and would have great positive effects on the basic research of disease and the design of new drugs.
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