Gproteinlinked receptors

The best known of the neurotransmitter receptors that act via G proteins are the muscarinic acetylcholine receptor and the ^-adrenergic receptor. There are a number of subtypes of each of these, as is indicated in Table 8.1. fl-adrenergic receptors mediate many of the responses to noradrenaline in smooth and heart muscle cells, as we shall see in Chapter 11.

Molecular cloning techniques show that the muscarinic acetylcholine receptor and the ^-adrenergic receptor (Fig. 8.10) are strikingly similar in structure, with identical amino acids at 30% of their residues. Their amino acid sequences are also surprisingly similar to that of the visual pigment rhodopsin, with 23% homology in each case. All three molecules have seven hydrophobic membrane-crossing segments. They form part of a large super-family of receptors, all with seven transmembrane segments. Different members of the superfamily respond individually to various neurotransmit-ters, neuropeptides, hormones, olfactory stimulants, or (for rhodopsin and other visual pigments) the isomerizations of retinal produced by light.

G proteins consist of three subunits, named a, fl and y. At rest they are in the trimeric form afly with GDP (guanosine diphosphate) bound tightly to the a subunit. When a neurotransmitter molecule binds to the receptor, the receptor interacts with the G protein so that it releases the GDP and binds GTP (guanosine triphosphate) in its fly subunit. The a subunit then binds to an effector molecule and activates it. Sometimes the fly subunit also acts as an activator. Fatty acid chains attached to the two subunits keep them in contact with the plasma membrane, so that they can shuttle between the receptor and the effector molecules.

The effector molecule is sometimes an ion channel, as occurs in the muscarinic action of acetylcholine on the heart. More commonly it is an enzyme whose activation leads to the production of a second messenger. Thus the membrane-bound enzyme adenylyl cyclase is activated by certain G proteins in order to make cyclic AMP from ATP. The cyclic AMP then activates the enzyme protein kinase A, which will result in the phosphorylation of some target molecule such as an ion channel.

An alternative route for G protein action is the phosphatidyl inositol signalling system. Here the G protein activates the enzyme phospholipase C, which hydrolyses the membrane phospholipid phosphatidyl inositol to

Fig. 8.9. Direct and indirect action of neurotransmitters on ion channels. a shows the direct action which occurs when the ion channel is an integral part of the receptor, as in the nicotinic acetylcholine receptor. In b and c the receptor molecule acts indirectly via activation of a G protein. In b the G protein acts directly on the channel to open or close it. In c the G protein activates an enzyme which generates a second messenger such as cyclic AMP which itself then alters the state of the channel. From Aidley (1998).

Fig. 8.9. Direct and indirect action of neurotransmitters on ion channels. a shows the direct action which occurs when the ion channel is an integral part of the receptor, as in the nicotinic acetylcholine receptor. In b and c the receptor molecule acts indirectly via activation of a G protein. In b the G protein acts directly on the channel to open or close it. In c the G protein activates an enzyme which generates a second messenger such as cyclic AMP which itself then alters the state of the channel. From Aidley (1998).

Table 8.1. Some neurotransmitter receptors

Transmitter lonotropic

Metabotropic

Acetylcholine

GABA

Glycine

5-hydroxytryptamine Glutamate

Noradrenaline

Dopamine

Neuropeptides

Nicotinic receptors GABAa receptor Glycine receptor 5-HT3 receptor

AMPA-kainate receptors NMDA receptors P2X receptor

Muscarinic receptors M1 to M5 GABAb receptor

5-HT124 receptors mGluR1 to mGluR5 receptors

P2Y receptor av a2, ¡51 and ¡2 receptors

D1-like and D2-like receptors

Rhodopsin-like (e.g. substance

P, enkephalin) Glucagon-receptor-like (e.g. VIP)

Notes:

Abbreviations: GABA, y-amino butyric acid; 5-HT, 5-hydroxytryptamine; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate; NMDA, N-methyl-d-aspartate; VIP, vasoactive intestinal polypeptide. lonotropic receptors have their own intrinsic ion channel and mediate fast synaptic transmission. Metabotropic receptors activate ion channels indirectly via G proteins and (usually) second-messenger systems.

produce diacyl glycerol and inositoltrisphosphate (IP3). The IP3 acts as a second messenger by activating calcium-release channels in the endoplasmic reticulum membrane, so raising the intracellular calcium ion concentration.

These systems clearly involve some considerable amplification. One receptor molecule binding a single neurotransmitter molecule can activate a number of G protein molecules, and each activated effector molecule will produce several second messenger molecules.

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