The neuron’s plasma membrane, crucial for neural function, exhibits selective permeability, notably high for potassium ions (K+) and lower for sodium ions (Na+). These ions are not in equilibrium; sodium is more concentrated outside the cell, while potassium is more concentrated inside. This concentration difference naturally drives diffusion: potassium out of the cell and sodium into it, following their electrochemical gradients. However, living neurons maintain these concentration gradients at a steady state, indicating an active compensatory mechanism: active transport by the sodium-potassium pump. This pump diligently moves sodium ions outwards, against their concentration gradient, and potassium ions inwards, ensuring the necessary ionic balance for neuronal activity.
This vital pump is a large protein complex embedded within the neuron’s plasma membrane. It features receptor sites facing both the cytoplasm and the extracellular environment. Intriguingly, the cytoplasmic side of the pump has a high affinity for sodium ions and a low affinity for potassium ions. Conversely, the extracellular side exhibits a high affinity for potassium and a low affinity for sodium. Triggered by the binding of these ions to their respective receptors, the pump actively transports them in opposite directions, working against their concentration gradients to maintain cellular disequilibrium.
The sodium-potassium pump’s action is not electrically neutral. In many neurons, it transports three sodium ions out of the cell for every two potassium ions it moves in. Variations exist, with some neurons exhibiting a 3:1 or even 2:1 sodium-to-potassium transport ratio. This unequal ion exchange results in a net positive charge efflux, contributing to the polarized state of the neuronal membrane, where the inner surface is slightly negative relative to the outer surface. This charge separation, or potential difference, across the membrane is why the sodium-potassium pump is described as electrogenic.
Crucially, the sodium-potassium pump performs active transport. This means that pumping ions against their concentration gradients demands energy from an external source. This energy source is adenosine triphosphate (ATP), the primary energy currency of the cell. ATP consists of an adenosine diphosphate (ADP) molecule linked to an inorganic phosphate molecule via a high-energy bond. The pump contains an enzyme, sodium-potassium-ATPase, which hydrolyzes ATP, splitting off the phosphate group. The energy released from this ATP hydrolysis powers the conformational changes in the pump protein, driving the active transport of sodium and potassium ions.
While the sodium-potassium pump establishes the neuron’s resting membrane potential by maintaining ionic disequilibrium through active transport, rapid changes in membrane permeability are responsible for neuronal signaling. The neuron’s transition from a resting to an active state, generating a nerve impulse, is triggered by a sudden influx of sodium ions into the cell. Given the plasma membrane’s relative impermeability to sodium, this influx implies a rapid alteration in membrane permeability. For many years, scientists hypothesized the existence of pores or channels in the membrane to facilitate ion diffusion across the lipid bilayer.
The groundbreaking development of the patch-clamp technique in the 1970s and 80s revolutionized our understanding. This technique allowed direct measurement of currents flowing through single ion channels in the membrane. By isolating a small patch of neuron or muscle cell membrane with a micropipette, researchers could record the minute electrical currents associated with the opening and closing of individual ion channels.
These studies revealed that ion channels are protein structures spanning the membrane, forming water-filled pores selective for specific ions. Some channels are “voltage-dependent,” activated by changes in membrane potential, while others are “neurotransmitter-sensitive,” responding to neurotransmitter binding. A key feature of these channels is the selectivity filter, a narrow region within the pore that dictates the channel’s specificity for a particular ion type.
Voltage-sensitive sodium channels, crucial for nerve impulse initiation, have been extensively studied. They are glycoproteins composed of four transmembrane domains surrounding a central pore. The selectivity filter, lined with negatively charged carbonyl oxygens, attracts cations while repelling anions. Within the channel, charged particles act as gates, controlling sodium ion diffusion in response to changes in membrane potential.
Potassium channels exhibit diversity, with multiple voltage-dependent types, each contributing to neuronal function. The delayed rectifier channel (IDR) facilitates potassium efflux following membrane depolarization, counteracting sodium influx and repolarizing the membrane, thus limiting the duration of nerve impulses. The A current (IA) channels, activated by depolarization after hyperpolarization, regulate neuronal firing frequency. Calcium-activated potassium channels (IK(Ca)) induce hyperpolarization upon increases in intracellular calcium, slowing repetitive firing. The IM channel, deactivated by acetylcholine, modulates neuronal sensitivity to synaptic inputs. Finally, the anomalous rectifier channel (IIR) promotes inward potassium diffusion upon hyperpolarization, prolonging depolarization and contributing to long-lasting nerve impulses.
Calcium channels, like potassium channels, are diverse, mediating slower inward calcium currents. Two main types exist in central nervous system neurons: long-lasting channels activated at positive potentials and transient channels activated at more negative potentials, reflecting different channel conductances and activation thresholds.
While less understood, anion channels, particularly chloride channels (Cl−), are also present. Patch-clamp recordings have confirmed voltage-dependent, high-conductance chloride channels in cultured tissues, with lower conductance channels also observed in neurons and artificial membranes.
In conclusion, the sodium-potassium pump, utilizing active transport, is fundamental for establishing and maintaining the ionic gradients essential for neuronal excitability and signaling. While active transport by the sodium-potassium pump sets the stage, passive transport through diverse ion channels orchestrates the rapid ionic fluxes underlying nerve impulses and neuronal communication. Both active and passive transport mechanisms are indispensable for the complex functioning of the nervous system.
