Voltage-gated ion channels

Functional units

Voltage-gated ion channels consist of subunits with transmembrane domains, which are arranged in such a way that there is a central pore. This pore serves as a route for the influx or efflux of selected ions through the membrane. The pore opens to the selected ion because the amino acids in the channel’s structure are sensitive to charge. All voltage-gated ion channels are made up of three main functional units:

1. The voltage sensor which detects membrane potential changes. It is composed of charged amino acid residues and changes conformation leading to either opening or closure of the channel in response to alterations in voltage.
2. The pore which acts as the conducting pathway for ions to pass. The ion selectivity of the channel is determined by the amino acid composition of the pore in conjunction with the charge and size of the ion.
3. The gates which control the channel’s opening and closing dynamics depending on the membrane potential. The activating gate typically opens in response to depolarization. In some channels, an inactivation gate is also present.

Voltage-gated Na⁺ channels

The core structure of voltage-gated Na⁺ channels is formed by an alpha (a) subunit, with four homologous domains (I-IV), each containing six transmembrane segments (S1-S6). The highly conserved S4 segment acts as the voltage-sensing domain, while segments S5-S6 and the intervening pore loop form the activation gate and the Na+ conducting pore. The region linking domains III and IV forms the inactivation gate of the channel. Alpha subunits, though functional on their own, can also bind to auxiliary proteins, such as beta (β) subunits, altering the voltage sensitivity, channel kinetics, and cellular localization of the channels.

Normally, the inner portion of the cell membrane is negatively charged at rest. This is due to the Na⁺/K⁺ ATPase activity, transporting three Na⁺ ions out of the cell and two K⁺ ions into the cell. This difference of charge is measured at -70 mV, a value described as the resting membrane potential. Any change in the potential across the membrane making the inside of the membrane less negative compared to the outside is called depolarization. Temporal and spatial summation of postsynaptic graded potentials at the receptive surface can bring the voltage from the resting membrane potential (-70 mV) to a threshold potential (-55 mV). When the cell membrane is depolarized to reach the threshold potential, an action potentialis initiated at the axon hillock, the so-called “trigger zone” of the neuron. Like a digital event, the action potential is an “all or none” phenomenon; any depolarization that does not reach the threshold will not result in an action potential. Stronger stimuli will initiate multiple action potentials more frequently, but the individual action potentials will peak at the same voltage (+30 mV).

Voltage-gated Na⁺ channels are high in concentration at the axon hillock and are responsible for the rapidly rising phase of the action potentials. The S4 voltage-sensing domain contains positively charged arginine or lysine residues in repeated patterns (motifs), facing the cytosol in the resting state. As the membrane depolarizes, the positively charged amino acids move outward. This movement triggers conformational changes and the activation gate opens in response to the threshold potential, allowing Na⁺ ions to rush into the cell. Timed with the depolarization peak at +30 mV, the inactivation gate closes, inhibiting Na⁺ ions from further entering the cell. Thus, the stimulus for the closure of the inactivation gate is also the initial depolarization; however, the closure is delayed, regulating the timing and the duration of the action potential.

Once an action potential has been initiated, a second one cannot be initiated. This phenomenon is referred to as the refractory period and has two phases:

1. the absolute refractory period, during which the cell is unable to initiate an action potential irrespective of the stimulus strength, as the voltage-gated Na⁺ channels are either already activated (depolarization) or inactivated (repolarization),
2. the relative refractory period, during which a stronger-than-usual stimulus can initiate an action potential, as the voltage-gated Na⁺ channels are back to their resting conformation, with the inactivation gate open, but the membrane is hyperpolarized.

The refractory period is key to the unidirectionality of the action potential propagation down the axon to the axon terminals, eliminating the possibility of an action potential moving back towards the soma.

Propagation of action potentials along the axon differs depending on the myelination state of the neuron. In unmyelinated neurons the conduction is continuous, along the entire length of the axon, causing the constant wave-like opening of voltage-gated Na⁺ channels of adjacent regions. In myelinated neurons, conduction is referred to as saltatory conduction (“to saltate”= to move by jumps or leaps). Voltage-gated Na⁺ channels are only present in the nodes of Ranvier, where the axon membrane is exposed, and, thus, the action potentials “jump” from node to node, bypassing the myelinated areas. This pattern of propagation allows for faster and more energy-efficient transmission.

Voltage-gated K⁺ channels

Voltage-gated K⁺ channels are made of four alpha (α) subunits, each contributing a transmembrane domain containing six transmembrane segments (S1-S6) and auxiliary subunits. Similar to the voltage-gated Na⁺ channels, the S4 segment acts as the voltage-sensing domain, and segments S5-S6 along with their connecting loop form the gate and the K⁺ conducting pore. The gate can be either open, to allow the outflow of intracellular K⁺ ions, or closed, to inhibit it.

Voltage-gated Ca²⁺ channels

Voltage-gated Ca²⁺ channels are heteromultimers, formed by an a1 subunit and auxiliary subunits (a2-δ, β and γ) modulating the channel’s voltage dependence and gating kinetics. The major subunit is a1, with four homologous domains (I-IV), each containing six transmembrane segments (S1-S6) which consist of the conduction pore, the voltage sensor and the gates (similarly to the voltage-gated Na⁺ channels). Voltage-gated Ca²⁺ channels of neurons are mainly located in presynaptic terminals and display a slight permeability to Na⁺ ions (1000-fold lower than to Ca²⁺). When an action potential (+30 mV) reaches the axon terminal, voltage-gated Ca²⁺ channels open, leading to the influx of Ca²⁺. The Ca²⁺ bind to proteins on the surface of synaptic vesicles, facilitating their fusion with the presynaptic membrane. This leads to the release of neurotransmitters or neuropeptides through exocytosis, which then diffuse across the synaptic cleft, before they reach the postsynaptic cell membrane where they bind selectively to their receptors to exert their action.

Voltage-gated Cl^- channels

There are several subtypes of voltage-gated Cl^- channels. In neurons, the opening of voltage-gated Cl^- channels is context-dependent, and their voltage sensitivity as well as the direction of Cl^- movement varies depending on the physiological context and their subtype. Voltage-gated Cl^- channels are often activated upon hyperpolarization, contributing to inhibitory postsynaptic potentials (IPSPs). This hinders the neuron from reaching the threshold potential before an action potential is fired.