Download Nicotinic receptor signaling in nonexcitable

Am J Physiol Cell Physiol 299: C885–C887, 2010;
doi:10.1152/ajpcell.00324.2010.
Editorial Focus
Nicotinic receptor signaling in nonexcitable epithelial cells: paradigm shifting
from ion current to kinase cascade. Focus on “Upregulation of nuclear
factor-␬B expression by SLURP-1 is mediated by ␣7-nicotinic acetylcholine
receptor and involves both ionic events and activation of protein kinases”
Andrzej Slominski
Department of Pathology and Laboratory Medicine, Health Science Center, University of Tennessee, Memphis, Tennessee
Nonneuronal Cholinergic System
ACh, an important neurotransmitter, is synthesized and
degraded in a regulated fashion by many, if not all types, of
nonneuronal cells and plays a role as an autocrine/paracrine
hormone and/or cytotransmitter (20, 34). These nonneuronal
cells, including keratinocytes (KCs), express nicotinic and
muscarinic receptors, activation of which by ACh or other
ligands affects many cellular functions that include proliferation, differentiation, apoptosis, adhesion, and migration (20,
34). This nonneuronal cholinergic system is an example of
more general neuroendocrine-like mechanisms that mediate
peripheral responses to environmental factors (31) and of
evolutionary conservation of neuroendocrine systems in the
periphery (32).
SLURP-1
SLURP-1 belongs to the Ly-6 protein superfamily that is
divided into two subfamilies based on the presence of a
glycophosphatidyl inositol (GPI)-anchored signal sequence, of
which secreted forms, such as SLURP-1, lack the GPI anchor
and include snake neurotoxins (18). SLURP-1 was isolated
from a variety of biological materials including human blood,
saliva, sweat, tears, and urine (1, 4, 16), and its gene and/or
protein expression has been identified in many tissues, including skin, bladder (17), lung, trachea, esophagus, stomach,
immune system, uterus, and cornea (21, 24, 26, 27). SLURP-1
has been shown to alter expression of cell cycle regulators and
differentiation markers and to activate caspases in human KCs
(7). SLURP-1 can also protect respiratory and oral epithelial
cells from nitrosamine-induced malignant transformation (2,
3). Notably, nAChRs in KCs regulate SLURP-1 production,
suggesting a physiologic interplay between the ACh and
Address for reprint requests and other correspondence: A. Slominski, Dept.
of Pathology and Laboratory Medicine, Health Science Center, Univ. of
Tennessee, 930 Madison Ave., Memphis, TN 38163 (e-mail: aslominski
@uthsc.edu).
http://www.ajpcell.org
SLURP-1 signaling (4), which is further substantiated by
homology in its amino acid composition to that of single
domain frog cytotoxin and snake venom neurotoxins, such as
␣-bungarotoxin.
Statement of the Problem
In this issue, Dr. Grando and colleagues continue their
studies on SLURP-1 and Ach and demonstrate that the mode of
interaction of SLURP-1 with ␣7-nAChR is agonist-like, and
that activation of ␣7-nAChR by SLURP-1 triggers the twocomponent signaling systems, coupling the ionic events and
protein kinase signaling cascades to upregulation of NF-␬B
expression (10). This study has exciting clinical and biological
implications on the nonneuronal activity of the peripheral
cholinergic system. These include the following two major
points and other considerations (Fig. 1).
The nAChRs mediate signaling mechanisms of novel noncanonical nicotinic ligands of the Ly-6 protein family. Specifically, a novel paradigm of regulation of KCs by nAChRs has
been discovered, indicating that SLURP-1 interacts with ␣7nAChR expressed in KCs as an allosteric agonist (15). This
was further substantiated by radioligand binding studies that
showed that SLURP-1 interacted with the ligand-binding site
of KC nAChRs, showing a higher affinity to the [3H]nicotinesensitive receptors, such as ␣7, compared with the [3H]epibatidine-sensitive non-␣7-nAChRs (7). A drawback of the studies, however, was a lack of experiments employing labeled
SLURP-1 peptide to confirm that it can be precipitated or
colocalized with the ␣7-subunit.
In relation to the SLURP-1 mechanisms of signaling and
biologic effects, the authors show that the SLURP-1 signal
emanates from kinases physically associated with ␣7, leading
to activation of kinase cascades. The authors of this study
could have done more whole cell patch-clamp recordings, but
this might not have been an appropriate approach for measuring SLURP-1 signaling in nonexcitable cells.
A new paradigm of signaling by nAChR is presented that
does not require membrane depolarization as occurs in neurons and muscles. Earlier, the authors identified a novel paradigm of nAChR-mediated coordination of the ionic and metabolic signaling events that allows a nicotinic agonist to simultaneously alter gene expression and induce reciprocal changes
in the cytoskeleton and contractile system of KCs (13). In the
current study, the authors show that a nonionic signaling
mechanism mediates upregulation of the NF-␬B gene expression by SLURP-1 downstream of ␣7-nAChR via coupling of
ionic events to protein kinase signaling cascades upon ␣7nAChR activation. Other pathways (e.g., Akt) that can regulate
0363-6143/10 Copyright © 2010 the American Physiological Society
C885
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IN THIS ISSUE, DR. GRANDO’S research group reports an agonistlike upregulation of nuclear factor-␬B (NF-␬B) expression by
SLURP (secreted mammalian Ly-6/urokinase plasminogen activator receptor-related protein)-1, which is mediated by ␣7nicotinic acetylcholine (ACh) receptors (nAChRs) and which
involves both ionic events and activation of protein kinases
(10). The elucidation of the mechanism for SLURP-1 signaling
in the nonexcitable cells opens a door for novel approaches to
pharmacologic regulation of the cellular functions controlled
by autocrine/paracrine actions of ACh.
Editorial Focus
C886
NF-␬B downstream of nAChR were not explored, and the
signal transduction pathways of SLURP-1 regulation of expression of transglutaminase type I cytokeratin 10, p21, and
caspase-3 in KCs (7) were also not addressed in this study.
It is expected that such issues will be assessed in future
studies, since the authors have previously demonstrated that
downstream of KC nAChRs, the signaling pathways can involve elevation of intracellular Ca2⫹, activation of the protein
kinase C isoforms, CaMKII, Jak2, phosphatidylinositol 3-kinase (PI3K), Akt, p38 MAPK, phospholipase C, Src, EGF
receptor kinase, Rac, and Rho as well as the Ras/Raf-1/MEK/
ERK pathway (5, 6, 11, 12, 14). Of note, the Raf/MEK/ERK
cascade can be activated independently of Ras in a PKCdependent manner (19) and PI3K is positively regulated by
Ca2⫹ via CaMKII (23).
Other considerations. NF-␬B is considered to be a master
regulator of the inflammatory, proliferative, differentiation,
and cell survival processes (reviewed in Ref. 22). NF-␬B is
also important in the development, prevention, and therapy of
cancer (33). NF-␬B activity is stimulated by many pathways
that converge on I␬B kinases, including the signaling pathways
activated by various cytokines, lipopolysaccharide (LPS), and
tumor necrosis factor-␣ (8, 9). In this context, the identification
of NF-␬B as a downstream target of SLURP-1/nAChR is of
considerable interest. These studies may also serve as an
example of interaction of different signaling pathways at a
common effector.
Applicability of This Work To Other Cell Types
The authors’ findings have important implications to other
cell types in which SLURP-1 has been detected: neurons (25),
epithelia (respiratory, digestive, and mucocutaneous), cornea,
fibroblasts, lymphocytes, uterus, bone, blood, saliva, tears,
AJP-Cell Physiol • VOL
sweat, and urine (4, 7, 15, 16, 21, 24, 26, 27, 30), and in
addition, its enhancement of survival of periodontal ligament
fibroblasts (30), and its contribution to the maintenance of
bronchial epithelial cell homeostasis (21) and immune functions and motility (28). Furthermore, nAChRs can regulate the
production and secretion of SLURP-1 in several cell types (4,
29), thus reciprocally arranged signaling that involves
SLURP-1 and nAChR could operate in cells that express both
components.
GRANTS
National Institutes of Health support (Grant AR052190) is acknowledged.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author.
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Editorial Focus
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