Abstract
No consensus has yet been reached regarding the order of substrate addition to the high-affinity Na+ -D-glucose cotransporter (SGLT1). This problem was addressed by computer-assisted derivation of the steady-state velocity equations characterizing the eight-state Na+:Na+:substrate (NNS) and Na+:substrate:Na+ (NSN) mechanisms of cotransport. A notable difference was found in their denominator expressions and used to device a new strategy aimed at model discrimination in which the initial rate data are recorded at fixed S and analyzed relative to the N dependence of transport using a Hill equation. According to this protocol, the values of the Hill coefficient (n(H)) should be finite at all S (1.0 < n(H) < or =2.0) or decrease down to a limit value of 1.0 at high S in the case of the NNS and NSN models, respectively. These key experiments were performed in rabbit intestinal brush border membrane vesicles and demonstrated that a Hill equation with n(H) = 2.0 best describes the steady-state kinetics of Na+ -glucose cotransport at all S. We therefore propose a kinetic mechanism whereby Na+ binding should occur with very strong cooperativity within a rapid equilibrium segment of the transport cycle and be followed by a slow isomerization step before glucose addition.
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