Abstract
BackgroundSignaling pathways include intricate networks of reversible covalent modification cycles. Such multicyclic enzyme cascades amplify the input stimulus, cause integration of multiple signals and exhibit sensitive output responses. Regulation of glycogen synthase and phosphorylase by reversible covalent modification cycles exemplifies signal transduction by enzyme cascades. Although this system for regulating glycogen synthesis and breakdown appears similar in all tissues, subtle differences have been identified. For example, phosphatase-1, a dephosphorylating enzyme of the system, is regulated quite differently in muscle and liver. Do these small differences in regulatory architecture affect the overall performance of the glycogen cascade in a specific tissue? We address this question by analyzing the regulatory structure of the glycogen cascade system in liver and muscle cells at steady state.ResultsThe glycogen cascade system in liver and muscle cells was analyzed at steady state and the results were compared with literature data. We found that the cascade system exhibits highly sensitive switch-like responses to changes in cyclic AMP concentration and the outputs are surprisingly different in the two tissues. In muscle, glycogen phosphorylase is more sensitive than glycogen synthase to cyclic AMP, while the opposite is observed in liver. Furthermore, when the liver undergoes a transition from starved to fed-state, the futile cycle of simultaneous glycogen synthesis and degradation switches to reciprocal regulation. Under such a transition, different proportions of active glycogen synthase and phosphorylase can coexist due to the varying inhibition of glycogen-synthase phosphatase by active phosphorylase.ConclusionThe highly sensitive responses of glycogen synthase in liver and phosphorylase in muscle to primary stimuli can be attributed to distinctive regulatory designs in the glycogen cascade system. The different sensitivities of these two enzymes may exemplify the adaptive strategies employed by liver and muscle cells to meet specific cellular demands.
Highlights
Signaling pathways include intricate networks of reversible covalent modification cycles
A prototypical example of such an enzyme cascade system is the regulation of glycogen phosphorylase (GP) and glycogen synthase (GS), enzymes involved in glycogen degradation and synthesis respectively [3,4,5,6]
Glycogen phosphorylase is more sensitive than glycogen synthase to cyclic AMP (cAMP), while the opposite is observed in liver
Summary
Signaling pathways include intricate networks of reversible covalent modification cycles. Regulation of glycogen synthase and phosphorylase by reversible covalent modification cycles exemplifies signal transduction by enzyme cascades. This system for regulating glycogen synthesis and breakdown appears similar in all tissues, subtle differences have been identified. Phosphatase-1, a dephosphorylating enzyme of the system, is regulated quite differently in muscle and liver Do these small differences in regulatory architecture affect the overall performance of the glycogen cascade in a specific tissue? To circumvent a futile cycle, simultaneous activation of glycogenolysis and glycogen synthesis is prevented through reciprocal regulation of glycogen phosphorylase and synthase activities by a unique regulatory network [5,6] This reciprocal regulation is identical in all tissues, there are subtle differences indicating distinctive adaptation strategies in different cell types. The steady state model incorporates the cascade structure, multi-step and zero-order effects and inhibitor sensitivity in response to cAMP and glucose
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have