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

386
Histamine
NH 2
HN
N
SECTION II
H 1 H 4 H 2 H 3
G q/11 G q/11 G i/o G s
+ – +
–
G i
AC
cAMP
ATP
NEUROPHARMACOLOGY
PIP 2
PLC
DAG + IP 3
PKA activity
PKC
activity
Ca 2+
Figure 14–15. Main signaling pathways for histamine receptors. Histamine can couple to a variety of G protein- linked signal transduction
pathways via four different receptors. The H 1
receptor and some H 4
receptors activate phosphatidylinositol turnover via
G q/11
. The other receptors couple either positively (H 2
receptor) or negatively (H 3
and H 4
receptor) to adenylyl cyclase activity via
G s
and G i/o
.
Neuropeptides are processed and stored in large, dense- core
vesicles (LDCVs; see Figure 14–7). The peptides may be colocalized
and released together with small molecule transmitters,
such as a biogenic amine. Multiple peptides may be co- localized
within the same neuron. As noted, some neurons may contain two or
more transmitters, including peptides, and their release can be independently
regulated.
In contrast to the biogenic amines or amino acids, peptide
synthesis requires transcription of DNA into mRNA and translation
of mRNA into protein. This takes place primarily in perikaria and the
resulting peptide is then transported to nerve terminals. Single genes
can, through the post- translational action of peptidases, give rise to
multiple neuropeptides. For example, proteolytic processing of
proopiomelanocortin (POMC) gives rise to, among other things,
ACTH, α and γ MSH, β- MSH, and β- endorphin (Figure 14–16). In
addition, alternative splicing of RNA transcripts may result in distinct
mRNA species. For example, calcitonin and calcitonin generelated
peptide (CGRP) are derived in specific tissues from the same
primary transcript.
Organization by Function. Since most peptides were identified initially
on the basis of bioassays, their names reflect these biologically
assayed functions (e.g., thyrotropin- releasing hormone and vasoactive
intestinal polypeptide). These names become trivial when more
ubiquitous distributions and additional functions are discovered.
Some general integrative role might be hypothesized for widely separated
neurons (and other cells) that make the same peptide.
However, a more parsimonious view is that each peptide has unique
messenger roles at the cellular level that are used repeatedly in biologically
similar pathways within functionally distinct systems.
Most neuropeptide receptors are GPCRs. In comparison to
GPCRs for smaller ligands such as biogenic amines and amino acids,
the extracellular domains of neuropeptide receptors play a larger role
in ligand binding. As seen with other transmitter systems, there are
often multiple subtypes of receptor for the same peptide transmitter
(Table 14–9). For example, there are five subtypes of receptor for
somatostatin and all inhibit adenylyl cyclase through an interaction
with G i
; they differ in their interaction with various somatostatin
analogs. The cloning of the major members of the opioid- peptide
receptors has revealed unexpected, and as yet unexplained, homologies
with receptors for somatostatin, angiotensin, and other peptides.
Multiple melanocortin receptors exist that respond to various peptides
derived from POMC. Not surprisingly, the receptor on adrenal