Ligand-gated ion channels

Structure

Ligand-gated ion channels are proteins embedded in the phospholipid bilayer of the cell membrane, typically composed of three to five subunits.

Each subunit comprises polypeptide chains that traverse the membrane multiple times. Depending on the amino acid sequence, which may be identical or varied in each subunit, the subunits assemble into homomultimers or heteromultimers, respectively.

The channel's overall structure encompasses two distinct functional domains: the ligand-binding domain and the transmembrane domain.

Ligands

Ligands that bind and activate ligand-gated ion channels are chemical molecules, with neurotransmitters being the primary representatives for the synapses of the nervous system. These molecules encompass a diverse range of substances, including amino acids, amines, acetylcholine, peptides, purines, bases and lipids. Some of the most common neurotransmitters include:

• Glutamate: This molecule is the most prevalent neurotransmitter among neuronal synapses and has an affinity for cation-selective channels. Ionotropic glutamate receptors are composed of four subunits, which can form either homotetramers (with identical subunits) or heterotetramers (with different subunits). When the neurotransmitter binds to the receptor, it triggers the opening of the channel and the influx of Na⁺ ions. This increase in intracellular Na⁺ concentration moves the membrane potential closer to the threshold, making glutamate-selective receptors excitatory in nature.
• Gamma-aminobutyric acid (GABA): GABA serves as the principal inhibitory neurotransmitter within the central nervous system, with an affinity for anion-selective channels. Ionotropic GABA receptors are heteropentamers, formed by different combinations of four subunits (α, β, γ, δ). Upon binding of GABA to its ionotropic receptor, the associated channel undergoes activation, facilitating the permeation of chloride anions. This leads to an increase in intracellular anion concentration, hyperpolarizing the membrane and inhibiting neuron activation.
• Acetylcholine: Present in both the central and peripheral nervous systems, including the neuromuscular junction and the autonomic nervous system, acetylcholine serves as a neurotransmitter that can activate ion channels in the postsynaptic membrane. The ionotropic acetylcholine receptors, also known as nicotinic receptors, function as non-selective cation channels. Comprising five different subunits (2α, β, γ, δ), these receptors form a heteropentamer configuration. Upon activation, these receptors initiate the opening of pores, resulting in an influx of cations, predominantly Na⁺. This influx contributes to the depolarization of the membrane potential. Thus, acetylcholine is recognized as an excitatory neurotransmitter.

Selectivity

The selectivity of ligand-gated ion channels extends to both the ligands that activate them and the ions that can pass through them. While most channels exhibit high specificity for their ligands and the type of ions they transmit, anions or cations, they are generally non-selective for a specific ion. This selectivity is achieved through several mechanisms.

• Affinity of the ligand to the receptor: The interaction between an ion channel and a ligand is characterized by a high degree of precision, dependent on their affinity. This interaction resembles a lock-and-key configuration between the ligand and the binding domain of the channel.

• Selectivity filter lining: Cation-selective receptors typically exhibit a negative charge lining on the wall of the pore, while anion-selective receptors present a positive charge lining. This arrangement ensures that only ions of the opposite charge are allowed to pass through the channel.

• Size and electrical charge of the ions: The atomic radius and electric charge of ions influence the selectivity of channels. Small ions may encounter difficulty passing through pores with large diameters, as they have limited interaction with the channel's walls. Conversely, large ions may struggle to pass through small pores due to their size. Additionally, the electrical charge of ions affects selectivity. Ions with smaller atomic radius exhibit higher charge density, resulting in a stronger attraction to water molecules and the formation of a hydration shell. This shell further impacts their ability to pass through the channel.

Permeability

Upon binding to the appropriate ligand, the associated channel undergoes a conformational change, facilitating the passage of ions across the cell membrane.

In the nervous system, the predominant ions traversing the cell membrane are sodium, calcium and potassium cations, as well as Cl^- anions. Ligand-gated ion channels can exhibit either cation selectivity or anion selectivity, depending on the electrical charge lining the channel pore. However, many channels are not exclusively selective for one specific ion. For example, the N-methyl-D-aspartate receptor (also known as NMDAR), a type of ionotropic glutamate receptors, permits the flow of Na⁺, Ca²⁺and K⁺ ions.

Activation of cation selective receptors, like ionotropic glutamate receptors, commonly leads to an intracellular accumulation of positive ions that shifts the membrane potential toward the threshold. Therefore, cation selective channels are considered to be excitatory. On the contrary, anion selective receptors, exemplified by those binding GABA, are considered to be inhibitory. The influx of anions elevates the concentration of negative ions within the cell, inducing membrane hyperpolarization.

However, it should be noted that all cations do not diffuse in equal numbers through the non-selective ligand-gated cation channels. This asymmetry is attributed to the reversal potential of the cell membrane. According to this phenomenon, each cation has an equilibrium potential, representing the point at which there is no net flow of ions in or out of the cell. The equilibrium is maintained by the symmetrical influence of electrochemical gradients acting on the ions. In the case of non-selective receptors permeable to multiple cations, the respective equilibrium potential is called reversal potential. The reversal potential is found somewhere in between the equilibria of permeable cations, signifying the point at which concentration and electrical gradient secure an equal influx across the membrane and zero alteration in membrane potential.

Roles

Ionotropic vs metabotropic receptors

In contrast to ligand-gated ion channels, which exhibit high affinity only for specific ligands, each ligand can bind to various receptors. Ionotropic and metabotropic receptors are the two main types of ligand receptors found on the surface of neurons, each type playing distinct roles in cellular signaling.

Ionotropic receptors are fast-acting ligand-gated ion channels that directly control ion passage upon binding with neurotransmitters. When a neurotransmitter binds to an ionotropic receptor, the receptor undergoes a conformational change that opens an ion channel, allowing ions to flow into or out of the cell. This rapid influx or efflux of ions results in a quick change in the cell's membrane potential, leading to fast synaptic transmission.

In contrast, metabotropic receptors are slower-acting receptors that indirectly modulate ion channels through intracellular signaling pathways. Upon neurotransmitter binding, metabotropic receptors activate a series of intracellular signaling cascades involving second messengers and protein kinases, ultimately leading to changes in gene expression, enzyme activity or ion channel function.

While ionotropic receptors mediate fast, transient responses, metabotropic receptors are involved in more prolonged and modulatory effects on cellular function, contributing to various physiological processes such as synaptic plasticity, learning, and memory. Thus, the interplay between ionotropic and metabotropic receptors allows for the precise regulation of neuronal activity and the integration of complex signaling pathways in the nervous system.