In a later lecture on the neuronal action potential, we will see that the action potential (i.e., electrical impulse) is responsible for much of communication in the nervous system, and that it involves a rapid reversal of the membrane potential such that the potential inside of the cell transiently becomes positive with respect to the outside before it returns back to the resting value (see action potential figure). We will also see that in order for a neuron to generate an action potential, the membrane potential has to depolarize from the resting value of around −70 mV to the threshold value of around −50 mV. A similar situation is also at play in muscle cells (skeletal, cardiac, and smooth). This is because it is at the threshold voltage that voltage-gated Na⁺ and K⁺ channels become activated. Thus, the normal generation of action potentials depends on a normal physiological value of the resting membrane potential. Importantly, the voltage-gated Na⁺ channels of neurons, skeletal muscle, and cardiac muscle cells enter an inactivated, non-conducting state after opening, and cannot reenter the open state without first recovering from inactivation (see figure). Recovery from inactivation is a voltage-dependent process that takes place at membrane potential values more negative than the threshold voltage. Thus, the return of the membrane potential to the resting value is critical for allowing these channels to continue to function properly. If due to a pathophysiological condition (such as elevated extracellular K⁺ levels), the resting membrane potential approaches the threshold potential for neuronal and muscle voltage-gated Na⁺ channels, the channels would enter the inactive state, from which they cannot recover. The consequence of this will be devastating for the organism in that neurons can no longer fire and cardiac myocytes can no longer contract to pump blood through the circulatory system. It should be clear that this situation will result in the death of the organism!

Another example that highlights the importance of the resting membrane potential is the influence of the value of the membrane potential on the activity of electrogenic transport proteins. As described in a previous lecture on secondary active transport, Na⁺-coupled cotransporters use the energy stored in the electrochemical gradient of Na⁺ to drive ions and molecules against an electrochemical or a concentration gradient across cell membranes. One example presented was the Na⁺/glucose cotransporter (SGLT), which couples the simultaneous cotranslocation of 2 Na⁺ ions and 1 glucose molecule across the apical membrane (i.e., brush border membrane) of epithelial cells in the small intestine (leading to glucose absorption) and kidney proximal tubules (leading to glucose reabsorption) (Fig. 1). In the small intestine, this process is essential for the absorption of glucose contained in ingested food across the wall of the small intestine. Once inside the cell, glucose leaves the cell down a concentration gradient via the activity of a facilitative glucose transporter (GLUT) present in the basolateral membrane. After transport across the wall of the small intestine, glucose enters the circulation via mucosal capillaries. In the kidneys, glucose is filtered out of the glomerular capillaries to enter the Bowman's space and later the lumen of the proximal tubule. In healthy individuals, all of the glucose present within the lumen of the proximal tubule is reabsorbed across the wall of the proximal tubule. Reabsorbed glucose then enters the peritubular capillaries to reenter the circulation.

Because 2 Na⁺ ions are moved during every transport cycle of the Na⁺/glucose cotransporter, the process is electrogenic and, thus, sensitive to the voltage difference across the plasma membrane (Fig. 2). As shown in a previous lecture, basic thermodynamic principles can be used to derive the equation that describes the thermodynamic equilibrium for transport (Equation 1). At thermodynamic equilibrium, no net transport of Na⁺ and glucose takes place across the plasma membrane. The membrane voltage at which the transporter is in thermodynamic equilibrium is referred to as the reversal potential (V_rev).

Similar to the concepts we described for the electrochemial driving force acting on ions, the resting membrane potential is rarely at the reversal potential for any given transport process and, therefore, the transporter is not at equilibrium at the resting potential of most cells. The magnitude of the difference between V_m and V_rev contributes to the driving force that acts on the transport process. In general for Na⁺-coupled transporters, if V_m is more negative than V_rev (i.e., V_m < V_rev), then the transporter works to translocate Na⁺ and glucose into the cell (referred to as the forward mode of transport). If V_m is more positive than V_rev (i.e., V_m > V_rev), then the transporter works to translocate Na⁺ and glucose out of the cell (referred to as the reverse mode of transport). Thus, the direction of transport can change (i.e., forward or reverse) and depends on the driving force acting on the transport process. Of course, there will be no net transport if V_m = V_rev. Under normal physiological concentrations, SGLT works in the forward mode to accumulate glucose inside the cell.

Since V_m is rarely at the V_rev for any given transport process, and since the intracellular and extracellular concentrations of Na⁺ are fairly well regulated within narrow limits (see table of ion concentrations), by working in the forward mode to transport glucose into the cell, the Na⁺/glucose cotransporter continues to accumulate glucose inside the cell in order to adjust the intracellular glucose concentrations such as to make its V_rev equal to V_m. Thus, the equation shown above can be rewritten to examine the concentrative capacity of the transporter (Equation 2). In this case, the concentrative capacity of SGLT can be described as the ratio of intracellular glucose concentration to extracellular glucose concentration. Therefore, the concentrative capacity simply provides a measure of how well a transporter can accumulate its substrate in the cell against a concentration gradient. Given that the intracellular and extracellular concentrations of Na⁺ are fixed by cellular homeostatic processes, it can be seen in Equation 2 that the membrane potential very strongly influences the concentrative capacity of the Na⁺/glucose cotransporter. This can also be shown graphically (Fig. 3).

It can be seen in Fig. 3 that the membrane potential provides significant free energy for glucose accumulation inside epithelial cells of the small intestine and kidney proximal tubules. For a typical cell with the resting membrane potential of −50 mV, the ratio of intracellular to extracellular glucose concentration is approximately 4,000. That is to say that SGLT can concentrate glucose inside the cell to a level approximately 4,000 times higher than the concentration outside the cell. Clearly, this represents active transport of glucose into the cell. Specifically, this is Na⁺-coupled secondary active transport because secondary active transporters use the energy stored in ion gradients and not through the hydrolysis of ATP as utilized by primary active transporters. In the small intestine, this has physiological significance for glucose absorption from food within the lumen of the small intestine. In the kidney proximal tubules, this contributes to complete glucose removal from the lumen before the ultrafiltrate moves beyond the proximal tubules (to enter the loop of Henle).