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 +,
• NMDA glutamate receptor (Na +, K+,
• ADP (Purine) receptor P2X (Na +, K+,
• Serotonin receptor 5-HT 3 (Na+,
• 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
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
• Catecholamine receptors (several types)
• Serotonin receptors 5-HT 1,2,4,6
• GABAB receptors
• `Metabotropic' glutamate receptors (11
• Purine receptors (P2Y): Adenosine, AMP, ADP,
• Peptide hormone receptors
Several things are of note
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
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.