Subunit transmembrane topology

The ligand-gated ion channel receptors form three distinct super-families based on the number of times the receptor subunits are predicted to cross the cell membrane (Fig. 3.2). For the nicotinic acetylcholine receptors, GABAa, GABAc, 5-HT3 and glycine receptors each subunit is predicted to cross the cell membrane four times (Fig. 3.2(a)). The exact transmembrane topology is only known with certainty for the nAChR (Unwin 1995). For the other 4-TM domain receptors (and for those in the 3-TM domain and 2-TM domain families) the transmembrane topology of each subunit has been inferred by analogy with the nAChR, from hydropathicity analysis of the subunit amino-acid sequence (about 20 hydrophobic amino acids are needed to form an alpha-helix long enough to span the cell membrane) and from experiments manipulating recombinant receptor subunits. All the 4-TM domain receptor subunits have both amino and carboxy terminals located on the outside of the membrane (Fig. 3.2(a)). The

Table 3.1 Fast neurotransmitters in the central nervous system

Transmitter

Ion channel receptors

G-protein-coupled receptors

Glutamate

Kainate

mGluR

AMPA

NMDA

GABA

gabaa

GABAB

GABAC

Acetylcholine

Nicotinic

Muscarinic

5-HT

5-HT3

5-HT

ATP

P2X

P2Y

Glycine

Gly-R

Except for glycine, all fast transmitters act on both ion channel receptors and G-protein-coupled receptors. Within each receptor class, there may be several subtypes.

Note:

Except for glycine, all fast transmitters act on both ion channel receptors and G-protein-coupled receptors. Within each receptor class, there may be several subtypes.

Pnr Medication Chart

Figure 3.2 Transmembrane (TM) topology of the subunits of three different super-families of ion channel receptors denoted as 4-TM, 3-TM and 2-TM receptors. In (a), the topology of the 4-TM domain subunits is illustrated embedded in the cell membrane. Receptors in this class are the nicotinic acetylcholine receptors, GABAa and GABAC receptors, glycine receptors and 5-HT3 receptors. Shown below is the likely pentameric stoichiometry of the 4-TM domain receptors with TM2 of each subunit lining the central ion channel. In (b), the transmembrane topology of the ionotropic glutamate receptors is shown. These have three true transmembrane domains. TM2 creates a pore-forming loop which penetrates into the cell membrane from the intracellular side. As illustrated below, the likely stoichiometry of the glutamate receptors is a tetramer. The exact contribution of TM1, TM3 or TM4 to forming the ion channel is uncertain. In (c), a subunit of the P2X ATP receptors is shown. These subunits cross the cell membrane only twice and the ion channel is probably formed by a short polypeptide loop entering the membrane from the outside. The exact stoichiometry of the P2X receptors is uncertain but current evidence supports the suggestion that they are trimers

Figure 3.2 Transmembrane (TM) topology of the subunits of three different super-families of ion channel receptors denoted as 4-TM, 3-TM and 2-TM receptors. In (a), the topology of the 4-TM domain subunits is illustrated embedded in the cell membrane. Receptors in this class are the nicotinic acetylcholine receptors, GABAa and GABAC receptors, glycine receptors and 5-HT3 receptors. Shown below is the likely pentameric stoichiometry of the 4-TM domain receptors with TM2 of each subunit lining the central ion channel. In (b), the transmembrane topology of the ionotropic glutamate receptors is shown. These have three true transmembrane domains. TM2 creates a pore-forming loop which penetrates into the cell membrane from the intracellular side. As illustrated below, the likely stoichiometry of the glutamate receptors is a tetramer. The exact contribution of TM1, TM3 or TM4 to forming the ion channel is uncertain. In (c), a subunit of the P2X ATP receptors is shown. These subunits cross the cell membrane only twice and the ion channel is probably formed by a short polypeptide loop entering the membrane from the outside. The exact stoichiometry of the P2X receptors is uncertain but current evidence supports the suggestion that they are trimers agonist binding site is located in the amino terminal domain before the start of TM1 and the ion channel is formed by the TM2 domains of each subunit which come together to make up the complete receptor. Thus the amino acids in TM2 determine the ion conductance properties of the channel. For GABA and glycine receptors a Cl_ channel is formed while for the other ion channel receptors, the channel is largely cation non-selective for monovalent ions such as Na+ and K+ and is often also permeable to calcium. One of the key differences between different ion channel receptors for glutamate, ACh, 5-HT and ATP is in their relative permeability to calcium and this is controlled by the amino acids which line the ion channel.

The ionotropic glutamate receptors (kainate, AMPA and NMDA) are formed by subunits which are predicted to cross the cell membrane three times (Fig. 3.2(b)) with the TM2 region forming a loop into the membrane from the intracellular side. The ionotropic glutamate receptor subunits have a large extracellular amino terminal domain and a long intracellular carboxy terminal domain (Fig. 3.2(b)). In the glutamate receptor subunits the agonist binding site is formed by a 'clam-shell' structure where the amino terminal domain and the extracellular domain between TM3 and TM4 come together to create a pocket for agonist binding.

The P2X receptor subunits are unusual in having only two transmembrane domains with both the amino terminal and carboxy terminal located intracellularly. The ion channel is proposed by analogy with the structure of some potassium channels to be formed by a short loop which enters the membrane from the extracellular side (North and Surprenant 2000).

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