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

TH
Dopa Tyrosine
197
Adrenergic
varicosity
AAADC
Dopamine MAO
AMP
VAMPS
Ca 2+ Ca 2+
Adenosine
ADP
rNTPase
P 1
ATP
NE
ATP
P2X 1 – P2X 7
NPY
ATP
NPY
NE
NPY
NE
ATP
Y 2
NPY
P2Y Y 1 – Y 5
NE
ATP
NPY
α 2
DA
DβH
NE
ATP
NE
Reserpine
NPY
α,β
NE
β 2
NE
Effector cell
membrane
Cocaine
Figure 8–6. An adrenergic neuroeffector junction showing features of the synthesis, storage, release, and receptors for norepinephrine
(NE), the cotransmitters neuropeptide Y (NPY), and ATP. Tyrosine is transported into the varicosity and is converted to DOPA by tyrosine
hydroxylase (TH) and DOPA to dopamine (DA) by the action of aromatic L-amino acid decarboxylase (AAADC). Dopamine is
taken up into the vesicles of the varicosity by a transporter, VMAT2, that can be blocked by reserpine. Cytoplasmic NE also can be
taken up by this transporter. Dopamine is converted to NE within the vesicle via the action of dopamine-β-hydroxylase (DβH). NE
is stored in vesicles along with other cotransmitters, NPY and ATP, depending on the particular neuroeffector junction. Release of the
transmitters occurs upon depolarization of the varicosity, which allows entry of Ca 2+ through voltage-dependent Ca 2+ channels.
Elevated levels of Ca 2+ promote the fusion of the vesicular membrane with the membrane of the varicosity, with subsequent exocytosis
of transmitters. This fusion process involves the interaction of specialized proteins associated with the vesicular membrane (VAMPs,
vesicle-associated membrane proteins) and the membrane of the varicosity (SNAPs, synaptosome-associated proteins). In this schematic
representation, NE, NPY, and ATP are stored in the same vesicles. Different populations of vesicles, however, may preferentially
store different proportions of the cotransmitters. Once in the synapse, NE can interact with α and β adrenergic receptors to produce
the characteristic response of the effector. The adrenergic receptors are GPCRs. α and β Receptors also can be located presynaptically
where NE can either diminish (α 2
), or facilitate (β) its own release and that of the cotransmitters. The principal mechanism by
which NE is cleared from the synapse is via a cocaine-sensitive neuronal uptake transporter, NET. Once transported into the cytosol,
NE can be re-stored in the vesicle or metabolized by monoamine oxidase (MAO). NPY produces its effects by activating NPY receptors,
of which there are at least five types (Y I
through Y 2
). NPY receptors are GPCRs. NPY can modify its own release and that of
the other transmitters via presynaptic receptors of the Y 2
type. NPY is removed from the synapse by metabolic breakdown by peptidases.
ATP produces its effects by activating P2X receptors or P2Y receptors. P2X receptors are ligand-gated ion channels; P2Y
receptors are GPCRs. There are multiple subtypes of both P2X and P2Y receptors. As with the other cotransmitters, ATP can act prejunctionally
to modify its own release via receptors for ATP or via its metabolic breakdown to adenosine that acts on P1 (adenosine)
receptors. ATP is cleared from the synapse primarily by releasable nucleotidases (rNTPase) and by cell-fixed ectonucleotidases.
CHAPTER 8
NEUROTRANSMISSION: THE AUTONOMIC AND SOMATIC MOTOR NERVOUS SYSTEMS