Department of Pharmacology and Toxicology and The Neuroscience Program, Michigan State University, East Lansing, Michigan 48824
COORDINATED CONTRACTION AND RELAXATION of gut smooth
muscle are essential for normal swallowing, gastric emptying,
intestinal propulsion, and defecation. Relaxation of gastrointestinal
smooth muscle is brought about by the action of inhibitory substances released by enteric nerves and other cells including interstitial cells
of Cajal and smooth muscle (3, 5, 6). Inhibitory neurotransmitters
include ATP, nitric oxide (NO), vasoactive intestinal peptide (VIP),
and pituitary adenylate cyclase-activating peptide (PACAP) (4, 6, 8).
The relative role of each of these substances in causing smooth muscle
relaxation varies across species and gastrointestinal tissues.
Neurotransmitter-induced relaxation of gastrointestinal smooth muscle
is associated with increases in intracellular cAMP and cGMP and
activation of apamin-sensitive, Ca2+-activated
K+ channels (4, 6, 9, 12). The
relative role of these multiple postjunctional mechanisms of relaxation
also varies across species and tissues and is a matter of intense
debate. One hypothesis proposed to account for the action of multiple
transmitters and mechanisms of relaxation in gastric smooth muscle
states that VIP and NO are coreleased by inhibitory nerves; NO acts
prejunctionally to facilitate further VIP release while VIP has two
postjunctional actions (5, 11, 12). First, VIP acts at
VIP2/PACAP3
receptors on gastric smooth muscle cells to increase intracellular cAMP via activation of the pertussis toxin (PTx)-insensitive G protein, Gs (9). Responses mediated at the
VIP2/PACAP3
receptor readily desensitize, and peptide histidine isoleucine is an
agonist at this receptor (9). VIP also acts at a second receptor
coupled via the PTx-sensitive G proteins,
Gi1-2, to an increase in
intracellular Ca2+ and activation
of a constitutive, membrane-bound form of NO synthase (eNOS). The
second VIP receptor desensitizes slowly and is peptide histidine
isoleucine insensitive. The increase in intracellular Ca2+ occurs following activation
of nifedipine-sensitive Ca2+
channels. Ca2+ activates eNOS in a
calmodulin-dependent manner, and NO stimulates soluble guanylate
cyclase to produce cGMP (9, 11, 12). Both cGMP and cAMP cause smooth
muscle relaxation. Support for this hypothesis is also based on the
localization of eNOS in smooth muscle cells using RT-PCR and Northern
blot analysis (14). One issue that remained unresolved was the identity
of the receptor at which VIP acts to stimulate eNOS. The article in
focus by Murthy et al. (Ref. 10, see p. C1408 in this issue) provides
strong evidence that VIP acts at the natriuretic peptide clearance
receptor (NPR-C) to activate nifedipine-sensitive, voltage-operated
Ca2+ channels with subsequent
stimulation of eNOS.
The NPR-C is a single-transmembrane domain receptor that lacks the
guanylate cyclase activity of other atrial natriuretic peptide (ANP)
receptors (7). The NPR-C was originally identified as a receptor
responsible for sequestration and degradation of circulating ANP (7).
However, the NPR-C can couple to
Gi and inhibition of adenylate
cyclase (2) . In guinea pig cecal smooth muscle cells, ANP
and VIP bind to a common receptor to cause relaxation, indicating that
VIP is an agonist at ANP receptors in gastrointestinal smooth muscle
(1). Murthy and co-workers (10) have established the specific ANP
receptor subtype at which VIP and ANP interact to cause smooth muscle
relaxation. Using rabbit dispersed gastric smooth muscle cells, they
showed that VIP, ANP, and the selective NPR-C agonist,
cANP-(4-23), cause relaxation through a signaling pathway
involving Gi1-2, activation
of nifedipine-sensitive Ca2+channels, an increase in
intracellular Ca2+, NOS
activation, and increases in cGMP. These responses were inhibited by
VIP and ANP receptor antagonists. Furthermore, the same pattern of
responses was produced in cells in which all receptors but the NPR-C
had been inactivated using a selective receptor-protection protocol.
Finally, the authors reconstituted the signaling pathway in COS-1 cells
cotransfected with NPR-C and eNOS, proteins not normally expressed by
these cells.
Murthy and colleagues have identified a novel pathway for activation of
eNOS in smooth muscle cells. However, these authors have left some
interesting questions unanswered about NPR-C-mediated regulation of
gastrointestinal smooth muscle. Relaxation caused by NPR-C activation
is dependent on activation of voltage-gated Ca2+ channels. It is unclear
whether the NPR-C mediates a cellular response leading to smooth muscle
depolarization and activation of
Ca2+ channels or whether the NPR-C
activates Ca2+ channels directly
through Gi1-2. It will also
be important to determine whether there is a functional relationship
between the NPR-C, eNOS, and cGMP mechanism of smooth muscle inhibition and other established mechanisms of neurogenic relaxation in intact tissues.
Murthy et al. (10) have proposed a scheme in which VIP
activates two signaling mechanisms to cause smooth muscle relaxation. One pathway involves activation of adenylyl cyclase and increases in
intracellular cAMP, whereas the second involves activation of eNOS and
increases in intracellular cGMP. These two pathways interact to
facilitate relaxation and to ensure that there are adequate mechanisms
in place to provide for efficient, nerve-mediated relaxation of smooth
muscle. Identifying the diversity of neurotransmitters producing
gastrointestinal smooth muscle relaxation has been a continuing focus
of research by enteric neurobiologists. However, Murthy et al. have
shown that the diversity of mechanisms for controlling smooth muscle
contractility is also expanded when a single transmitter (VIP) acts at
several postjunctional receptors that couple to multiple intracellular
signaling pathways. This adds to the array of mechanisms by which
enteric nerves and other cell types in the gastrointestinal tract
control smooth muscle function.
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