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Chapter: Biochemical Pharmacology : Drugs that act on sodium and potassium channels

Neurotransmitter receptors

The receptors for neurotransmitters fall into two broad classes: • Ligand-gated ion channels, and • G protein-coupled receptors (GPCR).

Neurotransmitter receptors

The receptors for neurotransmitters fall into two broad classes:


     Ligand-gated ion channels, and


     G protein-coupled receptors (GPCR).


Ligand-gated channels will respond to the binding of a spe-cific ligand with either opening or closing. We have seen an example of a ligand-gated channel before – the K ir/sulfony-lurea system. There, the physiological agonist (ATP) act-ed from within the cell and effected channel closure. With neurotransmitter receptor channels, the agonists act from outside the cell and will cause channel opening.


Ligand-gated channels (and their ion selectivities) include:


     Nicotinic acetylcholine receptor (Na +, K+, Ca++)


     NMDA glutamate receptor (Na +, K+, Ca++)


     ADP (Purine) receptor P2X (Na +, K+, Ca++)


     Serotonin receptor 5-HT 3 (Na+, K+, Ca++)


     Serotonin receptor MOD1 (Cl-)


     Glycine receptor (Cl-)


     GABAA receptor (Cl-)


Despite their different agonist and ion selectivities, all the above receptors belong to one homologous family and share the same overall structure. We will look in some detail at the workings of the nicotinic acetylcholine receptor in a subsequent chapter.

So what is the `nicotinic'acetylcholine receptor, and what is the `NMDA'glutamate receptor? These names reflect those of non-physiological agonists, nicotine and N-methyl-D-as-partate5, that selectively stimulate the receptors in question. Other types of receptors for acetylcholine or glutamate re-spond to different non-physiological agonists. As discussed previously, artificial agonists and agonists that exceed the natural agonists in receptor selectivity are important both for the experimental study of the receptors, and for applied pharmacotherapy.

The first four receptor channels listed above illustrate that the permeability of ligand-gated channels is not always very specific for one particular ion. In excitable cells, how-ever, the major effect with these receptors will be due to the increased permeability for Na+, because this will off-set the predominant effect of the K+ permeability on the resting potential. The effect of Ca++ permeability on the membrane potential will not be quite as great as that of Na+, because its concentration is much lower (cf. the Goldman equation). However, because the intracellular Ca++ concen-tration is normally very low, the Ca++ influx will suffice to increase it significantly. The Ca ++ influx therefore consti-tutes a biochemical signal that occurs simultaneously with the action potential.

The `prototype' (i.e., the most-studied example) of the ligand-gated synaptic channel is the nicotinic acetylcholine receptor; we will look at its workings in more detail in a later chapter. The other receptors listed are all structural-ly homologous to the nicotinic acetylcholine receptor and presumably work in much the same way. Interestingly, the NMDA receptor has binding sites for two different ligands – one for glutamate, and another one for glycine, which are located on separate subunits6 of the pentameric channel.


G protein-coupled receptors (GPCR) constitute the largest structural class of hormone and neurotransmitter receptors. They are sometimes also referred to as `metabotropic' re-ceptors, since they do not immediately affect the membrane potential but instead trigger biochemical cascades (which then, at a later stage, may yet alter the membrane potential, through ligand-gated channels that have intracellularly lo-cated binding sites for of G proteins or second messengers). Examples are:


     Muscarinic acetylcholine receptors (several types)


     Catecholamine receptors (several types)


     Serotonin receptors 5-HT 1,2,4,6


     GABAB receptors


     `Metabotropic' glutamate receptors (11 subtypes)


     Purine receptors (P2Y): Adenosine, AMP, ADP, ATP


     Peptide hormone receptors


Several things are of note here:


1.                 The vague phrase `peptide receptors' hides the fact that the number of peptide neurotransmitters (oxytocin, en-dorphin, cholecystokinine, galanin, …) is actually much larger than that of small molecules (comprising amino acids, amines, and acetylcholine). However, for most of these receptors, no specific agonists or antagonists are available, and they are therefore not presently in the fo-cus of pharmacotherapy to the same extent as the recep-tors for small molecular transmitters.


2.  Purine receptors: Adenosine, AMP, ADP and ATP can act extracellularly as hormones or transmitters, too! In particular, adenosine receptors that occur in the heart, the brain, and the lung are the targets of theophylline and caffeine. Adenosine itself is being used for the treatment of a special type of cardiac arrhythmia.


3.  Several transmitters – acetylcholine, glutamate, sero-tonin, GABA, and adenosine and its various phosphates

have receptors both among the ligand-gated channels and the G protein-coupled receptors. Thus, these trans-mitters evidently serve multiple purposes in the nervous system.


4.  Even among the G protein-coupled receptors respond-ing to one (hormone or) transmitter, there is consider-able variety, and the downstream signaling mechanisms employed by these various receptors may vary. E.g., among the 11 GPCR for glutamate, at least three down-stream signaling mechanisms are represented.


The various signalling mechanisms triggered by stimula-tion of GPCR will be discussed in more detail in a subse-quent chapter.

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