Solute Transport across Membranes:- The Acetylcholine Receptor Is a Ligand-Gated Ion Channel

Another very well-studied ion channel is the nicotinic acetylcholine receptor, essential in the passage of an electrical signal from a motor neuron to a muscle fiber at the neuromuscular junction (signaling the muscle to contract). (Nicotinic receptors were originally distinguished from muscarinic receptors by the sensitivity of the former to nicotine, the latter to the mushroom alkaloid muscarine. They are structurally and functionally different.) Acetylcholine released by the motor neuron diffuses a few micrometers to the plasma membrane of a myocyte, where it binds to the acetylcholine receptor. This forces a conformational change in the receptor, causing its ion channel to open. The resulting inward movement of positive charges depolarizes the plasma membrane, triggering contraction. The acetylcholine receptor allows Na⁺, Ca²⁺, and K⁺ to pass through with equal ease, but other cations and all anions are unable to pass. Movement of Na through an acetylcholine receptor ion channel is unsaturable (its rate is linear with respect to extracellular [Na+]) and very fast—about 2x10⁷ ions/s under physiological conditions.

This receptor channel is typical of many other ion channels that produce or respond to electrical signals: it has a “gate” that opens in response to stimulation by a signal molecule (in this case acetylcholine) and an intrinsic timing mechanism that closes the gate after a split second. Thus, the acetylcholine signal is transient— an essential feature of electrical signal conduction. We understand the structural changes underlying gating in the acetylcholine receptor, but not the exact mechanism of “desensitization”—of closing the gate even in the continued presence of acetylcholine.

The nicotinic acetylcholine receptor has five sub units: single copies of subunitsβ, α, and δ, and two identical subunits each with an acetylcholine-binding site. All five subunits are related in sequence and tertiary structure, each having four transmembrane helical segments (M1 to M4) (Fig. 11–51a). The five subunits surround a central pore, which is lined with their M2 helices. The pore is about 20 Å wide in the parts of the channel that protrude on the cytoplasmic and extra cellular surfaces, but narrows as it passes through the lipid bilayer. Near the center of the bilayer is a ring of bulky hydrophobic side chains of Leu residues in the M2 helices, positioned so close together that they prevent ions from passing through the channel. Allosteric con formational changes induced by acetylcholine binding to the two subunits include a slight twisting of the M²⁺ helices (Fig. 11–51b), which draws these hydrophobic side chains away from the center of the channel, opening it to the passage of ions. Based on similarities between the amino acid sequences of other ligand-gated ion channels and the acetylcholine receptor, the receptor channels that respond to the extracellular signals -aminobutyric acid (GABA), glycine, and serotonin have been classified in the acetylcholine receptor superfamily, and probably share three-dimensional structure and gating mechanisms. The GABA_A and glycine receptors are anion channels specific for Cl- or HCO^-₃, whereas the serotonin receptor, like the acetylcholine receptor, is cation-specific. The subunits of each of these channels, like those of the acetylcholine receptor, have four transmembrane helical segments and form oligomeric channels.

A second class of ligand-gated ion channels respond to intracellular ligands: 3,5-cyclic guanosine mono nucleotide (cGMP) in the vertebrate eye, cGMP and cAMP in olfactory neurons, and ATP and inositol 1,4,5 trisphosphate (IP3) in many cell types. These channels are composed of multiple subunits, each with six trans membrane helical domains.

FIGURE 11–51 Structure of the acetylcholine receptor ion channel. (a) Each of the five subunits (α₂βγδ) has four transmembrane helices, M1 to M4. The M2 helices are amphipathic; the others have mainly hydrophobic residues. The five subunits are arranged around a central transmembrane channel, which is lined with the polar sides of the M2 helices. At the top and bottom of the channel are rings of negatively charged amino acid residues. (b) This top view of a cross section through the center of the M2 helices shows five Leu side chains (one from each M2 helix) protruding into the channel, constricting it to a diameter too small to allow passage of ions such as Ca²⁺, Na⁺, and K⁺. When both acetylcholine receptor sites (one on each α subunit) are occupied, a conformational change occurs. As the M2 helices twist slightly, the five Leu residues (yellow) rotate away from the channel and are replaced by smaller, polar residues (blue). This gating mechanism opens the channel, allowing the passage of Ca²⁺, Na⁺, or K⁺.

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