Biomedical Engineering Reference
In-Depth Information
Presynaptic
Metabolite
Precursor
E
M
Ion channel
E
B
Storage
Uptake
Release
Presynaptic receptor
Autoreceptor
Degradation product
E
D
Postsynaptic receptors
E
SM
Ion channel
Second messenger
Postsynaptic
FIGURE 12.2
Generalized schematic illustration of processes and mechanisms associated with an axosomatic
synapse in the CNS. E, enzymes; E
M
, metabolic; E
B
, biosynthetic; E
D
, degradation; E
SM
, second messenger;
(
) neurotransmitter.
of the receptor, which remove the signaling molecule from the extracellular to the intracellular space,
where it is either stored or metabolized. The blockade of a transporter or a metabolic enzyme will
cause an elevation of the extracellular concentration of the signaling molecule and lead to increased
receptor activation, and transporters and metabolic enzymes can thus be viewed as indirect recep-
tor targets. Synaptic functions may also be facilitated by the stimulation of the neurotransmitter
biosynthesis, for example, by administration of a biochemical precursor. Transport mechanisms
in synaptic storage vesicles (Figure 12.2) are also potential sites for pharmacological intervention.
Autoreceptors normally play a key role as a negative feedback mechanism regulating the release of
certain neurotransmitters, making this class of presynaptic receptors therapeutically interesting.
Pharmacological stimulation or inhibition of the earlier mentioned synaptic mechanisms are,
however, likely to affect the function of the entire neurotransmitter system. Activation of neu-
rotransmitter receptors may, in principle, represent the most direct and selective approach to the
stimulation of a particular neurotransmitter system. Furthermore, activation of distinct subtypes
of receptors operated by the neurotransmitter concerned may open up the prospect of highly selec-
tive pharmacological intervention. Nevertheless, indirect mechanisms of targeting receptors via
regulation of the level of the endogenous agonist at the site-of-action remains an important pharma-
cological principle, which has also been applied outside the synapse as exemplii ed by compounds
increasing insulin release and preventing GLP-1 breakdown.
Direct activation of receptors by full agonists may result in rapid receptor desensitization (insen-
sitive to activation). Partial agonists are less liable to induce receptor desensitization and may there-
fore be particularly interesting for neurotransmitter replacement therapies. Desensitization may be a
more or less pronounced problem associated with the therapeutic use of receptor agonists, whereas
receptor antagonists, which in other cases have proved useful therapeutic agents, may inherently
cause receptor supersensitivity. The presence of allosteric binding sites at certain receptor com-
plexes, which may function as physiological modulatory mechanisms, offer unique prospects of
