DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

of multiple members of this receptor class reveals significant
homology among the amino acids in the
hydrophobic membrane spanning domains. Sites for N-
linked glycosylation are found on the extracellular
amino tail and sometimes on the second extracellular
loop. There are also multiple potential sites for phosphorylation
on the third intracellular loop and the carboxy
tail. Finally, some members of this class of
receptors are palmitoylated on the carboxy tail. When
this occurs, the carboxy tail is pulled toward the membrane
and becomes relatively fixed in position (Figure
14–6). GPCRs are associated with a broad spectrum of
physiological effects including activation of K + channels,
activation of PLC- IP 3
-Ca 2+ pathways and modulation
of adenylyl cyclase activity. The interaction of
GPCRs with effectors is regulated by a multiplicity of
G- proteins, each a heterotrimer of α and βγ subunits.
The GTP-binding α subunits modulate the activities of
numerous effectors (e.g., adenylyl cyclase, PLC). The
βγ subunits are also active, especially in the regulation
of ion channels. G 0
is prominant in the CNS and in sensory
neurons, G gust
mediates stimulation of taste receptors,
G olf
mediates olfaction, and transducin mediates
photo- transduction. The G protein activation-inactivation
is described in Chapter 3.
Strategies involving mutagenesis have defined how activated
receptors (themselves subject to reversible phosphorylation
at one or more functionally distinct sites) can interact
with heterotrimeric GTP- binding protein complex. GPCRs
include muscarinic cholinergic receptors, subtypes of GABA and
glutamate receptors, and many other aminergic and peptidergic
receptors. Transfecting cells lacking GPCRs with mRNAs for
GPCRs with no known ligands has led to the identification of
novel neuropeptide ligands for these “orphan” receptors (Robas
et al., 2003).
A third receptor motif is seen with a variety of
growth factor receptors (GFR); these are typically
monospanning membrane proteins that have an extracellular
binding domain that regulates an intracellular
catalytic activity, often a protein tyrosine kinase
(Figure 14–5C). These receptors are generally active
as dimers and possess intrinsic tyrosine kinase activity.
Following binding of an agonist ligand, dimerization of
the receptor occurs, resulting in receptor autophosphorylation.
The phosphorylated receptor recruits cytoplasmic
proteins leading to multiple protein- protein
interactions and activation of signaling cascades
(Chapter 3). Receptors with intrinsic guanylyl cyclase
activity rather than protein kinase activity are a variation
on this theme; an example is the atrial natriuretic
peptide (ANP) receptor.
A distinct class of receptors transduces steroid
hormone signaling. Steroid hormones cross cell membranes
and bind to cytoplasmic receptors. After nuclear
translocation these receptors bind DNA and function as
transcriptional regulators (Figures 14–5D and 6–12).
Postsynaptic receptivity of CNS neurons is regulated dynamically
in terms of the number of receptor sites and the threshold
required to generate a response. Receptor number often depends on
the concentration of agonist to which the target cell is exposed. Thus,
chronic exposure to an agonist can lead to a reduction in responsiveness
and in the number of receptors (desensitization and downregulation)
and consequently to subsensitivity or tolerance to the
transmitter. Conversely, denervation or the administration of an
antagonist can lead to supersensitive responses partially mediated
by an increase in the number of receptors. For many GPCRs, downregulation
is achieved by the actions of receptor kinases (GRKs) that
phosphorylate agonist occupied receptors leading in turn to internalization
of the receptors (Chapter 3).
CELL SIGNALING AND SYNAPTIC
TRANSMISSION
Most cell- to- cell communication in the CNS involves
chemical transmission (see Chapter 8). Chemical transmission
requires several discreet specializations
(Figure 14–7):
1. Transmitter synthesis. Small molecules like ACh
and NE are synthesized in nerve terminals; peptides
are synthesized in cell bodies and transported
to nerve terminals.
2. Transmitter storage. Synaptic vesicles store transmitters,
often in association with various proteins
and frequently with ATP.
3. Transmitter release. Release of transmitter occurs
by exocytosis. Depolarization results in an influx
of Ca 2+ , which in turn appears to bind to proteins
called synaptotagmins. An active zone is established
to which vesicles dock and then fuse with
scaffolding proteins on the presynaptic membrane.
After fusing with the membrane and exocytotic
release of their contents, synaptic vesicle proteins
are recycled through endocytosis (see Figures 8–2,
8–3, and 8–5).
4. Transmitter recognition. Receptors exist on post -
synaptic cells, which recognize the transmitter.
Binding of a neurotransmitter to its receptor initiates
a signal transduction event, as previously
described.
5. Termination of action. A variety of mechanisms terminate
the action of synaptically released transmitter,
including hydrolysis (for acetylcholine and
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CHAPTER 14
NEUROTRANSMISSION AND THE CENTRAL NERVOUS SYSTEM