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This inaugural lecture by H.R. Kaback explores the role of bioenergetics in energy-transducing membranes and its connection to various cellular processes. Topics include epithelial transport and synaptic function in the CNS.
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Bioenergetics in energy-transducing membranes represents the bridge between biochemistry and physiology. While ATP is the currency of energy exchange in the cytosol, electrochemical ion gradients across energy-transducing membranes are involved in a large number of seemingly unrelated processes such as oxidative phosphorylation, active transport of many different metabolites, signal transduction, maintenance of internal pH, intracellular organelle function, protein secretion, bacterial motility, and other cellular processes.
Epithelial transport. Transport across the epithelium of the intestine will be discussed briefly merely to demonstrate the similarity of the basic principles. The topic will be discussed in more detail by Professor Wright. At the lumenal or brush-border side of this polarized intestinal epithelial cell (top), sodium and glucose are symported via a sodium-coupled symport protein (SGLT1), leading to accumulation of glucose against a large concentration gradient in the cytosol. The accumulated glucose is then allowed to flow down its chemical gradient via a glucose uniporter (a.k.a., facilitated diffusion carrier) on the basolateral surface (bottom) into the serosal fluid, and sodium is pumped out on the basolateral surface by the Na+/K+-ATPase. The tight junctions keep the membrane proteins on the brush border from mixing with the proteins on the basolateral membrane and vice versa.
Synaptic function in the CNS.At neuromuscular junction, acetylcholine is released from pre-synaptic cells and binds to the nicotinic acetylcholine receptor on the muscle cell membrane, thereby opening a sodium channel which leads to depolarization of the post-synaptic muscle cell. Subsequently, the signal is terminated by acetylcholine esterase which hydrolyzes the neurotransmitter, and in addition, the acetylcholine receptor becomes desensitized. In contrast, at synapses in the CNS, the primary means of terminating the signal is by re-uptake of neurotransmitters (e.g., dopamine, serotonin, glutamate, glycine) into the pre-synaptic cell and subsequent repackaging into synaptic vesicles.
The next three lectures* will focus primarily upon one aspect of bioenergetics, active transport of metabolites in a specific experimental model system, bacterial cytoplasmic membrane vesicles, which revolutionized the field by leading to the development of similar systems from epithelia and the nervous system. The intent is to use this highly defined system to give you a feel for what an electrochemical ion gradient is, how the components are measured in microscopic systems that are not readily amenable to electrophysiology and how one can demonstrate convincingly that an electrochemical ion gradient is the immediate driving force for the accumulation of metabolites. The general relevance of this relatively simple experimental system to more complex systems that have direct relevance to human physiology will be illustrated.
Reading:Lectures from Professors Bezanilla and Wright contain related information that will help you understand the concepts under consideration.For those of you who would like more in-depth reading, the following are suggested: Kaback, H.R. 1971. Bacterial membranes. Methods in Enzymology 22, 99-130; Nichols, D. G. and Ferguson, S. 1992. Bioenergetics 2 (Academic Press, London).
