Cell Biology Poster Session



Materials & Methods


Discussion & Conclusion



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Regulation of ground squirrel Na+K+-ATPase activity by reversible phosphorylation during hibernation.

Contact Person: Justin MacDonald (jmacdona@ccs.carleton.ca)

Discussion and Conclusion

Among other remarkable properties, hibernating mammals display the ability to maintain appreciable cell function at low body temperatures. The ability to maintain the energy status of the cell during hibernation requires a suppression and coordination of both ATP-utilizing and ATP-consuming processes such that energy charge is maintained at a high and constant level. In S. lateralis, ATP levels are reduced in hibernation, but at the expense of the total adenylate pool rather than the energy charge. The maintenance of the energy charge in skeletal muscle during hibernation in ground squirrels and other hibernators implies that adenylate metabolism is regulated during hibernation. The lack of IMP build-up suggests that the mechanism of adenylate depletion different from the one that typically acts in skeletal muscle during exercise (12). During burst muscle work AMP deaminase helps to stabilize elevated energy charge by pulling AMP out of the pool as it builds up and converting it to IMP and ammonium ion. The formation of the latter is also a sink for protons that are accumulated during anaerobic glycolysis.

ATP-driven, transmembrane ion pumping consumes a huge fraction of total cellular energy use in mammals and the heat released during ATP hydrolysis is a major contributor to the high body temperature of endotherms (4). Not surprisingly, then, the activities of membrane ion pumps, particularly Na+K+-ATPase, are strongly regulated via several mechanisms. Na+K+-ATPase in mammalian skeletal muscle is under the control of a number of circulating hormones that impart both short- and long-term control over its activity (4). Long-term regulation occurs under the influence of thyroid hormone and aldosterone and is mediated by changes in gene expression, whereas short term regulation is exerted by catecholamines and mediated by reversible phosphorylation of the pump catalytic subunit (13).

For the hibernator, control over Na+K+-ATPase and other ion pumps and ion channels involved in transmembrane ion movements is particularly important since the transition to the hypothermic, hypometabolic state requires strict inhibitory controls over these processes for two reasons: 1) to facilitate the drop in body temperature by inhibiting thermogenic processes, and 2) to preserve transmembrane ion gradients at much lower body temperatures despite much lower rates of ATP production which, for nonhibernating mammals, cause massive disruption of ion homeostasis. Hence, a regulated transition to the hypometabolic, hibernating state requires strong regulatory control on Na+K+-ATPase in the tissues of hibernators but, nonetheless, a control mechanism that can be rapidly reversed to facilitate a quick return to euthermic conditions during periodic arousals from hibernation. For this type of control, the reversible regulation offered by protein phosphorylation/dephos-phorylation seems well suited and, indeed, the present data provide strong evidence that reversible phosphorylation is the major mechanism responsible for the hibernation-induced suppression of Na+K+-ATPase activity, at least in skeletal muscle. Long term changes in total enzyme content in tissues over the hibernating season may also have some role to play in the process, although these were not specifically investigated in the present study. However, it can be noted from Figure 5 that alkaline phosphatase treatment of muscle extracts raised Na+K+-ATPase maximal activity to only about 6.8 U/mg protein in extracts from hibernators compared with the >10 U/mg protein seen after comparable treatment of extracts from euthermic animals. This could suggest a difference in total enzyme content between the two states.

Additional factors may also play a role such as a cold-acclimation, such as a hibernation-dependent decrease in total Na+K+-ATPase (resulting from membrane vesicularization and/or proteolytic degradation, or from enzyme oxidation in hibernator tissues). However, given the key role of Na+K+-ATPase in the heat generation associated with shivering thermogenesis, it is logical to assume that hibernating animals would retain a high potential Na+K+-ATPase activity while torpid so that the enzyme could be rapidly activated during the arousal process. Hence, a rapidly reversible control mechanism such as protein phosphorylation would be highly effective for masking or inhibiting enzyme activity during torpor without changing total enzyme potential.

Cellular ion gradients are maintained, or at least are more slowly dissipated, in successful metabolic depression during hibernation (14,15). For example, erythrocytes of hibernating species, notably ground squirrels, maintain their Na+ and K+ gradients better at 5°C partly by decreases in the passive loss of K+ and gain of Na+ and partly by a relatively faster Na+K+-pump activity at 5°C than found in cells of a mammal with typical cold sensitivity (e.g. guinea-pig or human) (16). The ability to maintain ion gradients at hibernating body temperatures and the suppression of Na+K+-pump activity may protect tissues from the deleterious effects of ATP starvation. The key is the coordination of all factors to produce a net balanced metabolic suppression by targeting may different key points of metabolism. Interestingly, this can all apparently be achieved by reversible phosphorylation acting on a wide variety of different cellular targets.

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MacDonald, J.A.; Storey, K.B.; (1998). Regulation of ground squirrel Na+K+-ATPase activity by reversible phosphorylation during hibernation.. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Available at URL http://www.mcmaster.ca/inabis98/cellbio/macdonald0174/index.html
© 1998 Author(s) Hold Copyright