Calcitonin gene-related peptide- and adrenomedullin-induced facilitation of calcium current in submandibular ganglion.

Abstract

The control of saliva secretion is mainly under parasympathetic control. The submandibular ganglion (SMG) is a parasympathetic ganglion which receives inputs from preganglionic cholinergic neurons, and innervates the submandibular salivary gland to control saliva secretion. The aim of this study was to investigate if adrenomedullin (ADM) and/or calcitonin gene-related peptide (CGRP) modulate voltage-dependent calcium channel (VDCCs) current (I(Ca)) in SMG.
The profile of CGRP and ADM actions in SMG was studied using the whole-cell configuration of the patch-clamp technique.
Both ADM and CGRP facilitated I(Ca). These facilitations were attenuated by intracellular dialysis of the anti-Gα(s)-protein and pretreatment of SQ22536 (an adenylate cyclase inhibitor).
ADM and CGRP facilitates VDCCs mediated by Gα(s)-protein and adenylate cyclase in SMG.

Full text

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Posted at the Institutional Resources for Unique Collection and Academic Archives at Tokyo Dental College,
Available from http://ir.tdc.ac.jp/
Title
Cal ci toni n gene-rel ated pepti de- and
adrenom edul l i n-i nduced faci l i tati on of cal ci um
current i n subm andi bul ar gangl i on
Author(s)
Alternative
Endoh, T; Shi bukaw a, Y; Tsum ura, M ; Ichi kaw a, H ;
Tazaki , M ; Inoue, T
J ournalArchi ves of oral bi ol ogy, 56(2): 187-193
URLhttp: //hdl . handl e. net/10130/2232
Right

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Archives of Oral Biology (AOB-D-10-00132R1) Re-revised version

Calcitonin gene-related peptide- and adrenomedullin-induced facilitation of calcium
current in submandibular ganglion

Takayuki Endoha,*, Yoshiyuki Shibukawaa, Maki Tsumuraa,b, Hideki Ichikawaa,
Masakazu Tazakia, Takashi Inouea

aOral Health Science Center HRC7, Tokyo Dental College, 1-2-2 Masago, Mihama-ku,
Chiba 261-8502, Japan
bDepartment of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Toho University,
Japan
* Corresponding author. Tel.: +81 43 270 3771; fax: +81 43 270 3771
E-mail addresses: tendoh@tdc.ac.jp (T. Endoh)
24 pages
5 figures and figure legends (in Black/White)
Keywords: Saliva secretion, Submandibular ganglion, Calcitonin gene-related peptide,
Adrenomedullin, Ca2+ channels, adenylate cyclase

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ABSTRACT

Objective: The control of saliva secretion is mainly under parasympathetic control. The
submandibular ganglion (SMG) is a parasympathetic ganglion which receives inputs
from preganglionic cholinergic neurons, and innervates the submandibular salivary
gland to control saliva secretion. The aim of this study was to investigate if
adrenomedullin (ADM) and/or calcitonin gene-related peptide (CGRP) modulate
voltage-dependent calcium channel (VDCCs) current (ICa) in SMG.
Design: The profile of CGRP and ADM actions in SMG was studied using the whole-cell
configuration of the patch-clamp technique.
Results: Both ADM and CGRP facilitated ICa. These facilitations were attenuated by
intracellular dialysis of the anti-Gα s-protein and pretreatment of SQ22536 (an
adenylate cyclase inhibitor).
Conclusions: ADM and CGRP facilitates VDCCs mediated by Gα s-protein and
adenylate cyclase in SMG.

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1. Introduction

Capsaicin-sensitive primary afferents (CSPAs) are the C fibers which are specifically
activated by capsaicin, the pungent agent in red hot pepper 1. The CSPA release
transmitters such as CGRP and tachykinins from peripheral endings via local axon
reflex 1,2. In most species, the coexistence of CGRP with substance P (SP) in the
trigeminal supply of sensory capsaicin-sensitive nerves to the submandibular salivary
gland has been demonstrated 1,3. These fibers are seen around blood vessels, secretory
ducts, and the acini of submandibular gland 4. The majority of CGRP-immunoreactive
nerve fibers in the gland originate from neurons of the trigeminal ganglion 4. The
CSPAs, which are also nociceptive afferent nerves, regulate various peripheral
functions by neuropeptides which they release; vasodilation, extravasation of plasma
protein and blood cells, chemotaxis and phagocytosis of macrophages and neutrophils,
the production of arachidonate metabolites, and the activities of autonomic ganglia 5. In
the sphenopalatine ganglion, the SP and CGRP positive sensory nerves surround the
parasympathetic neuronal somata. The varicose appearance of the neuronal profiles
close to the ganglion cells suggests the presence of synapses en passant in the ganglion 1.
The submandibular ganglia contain CGRP-immunoreactive nerve fibers, but the

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ganglion cells are not immunoreactive for CGRP 4. Since CGRP is a potent vasodilator,
it is possible that these fibers have a role in regulation of the glandular blood flow, but
their exact functional roles in the parasympathetic ganglia remain to be established.
The submandibular ganglion (SMG) is a parasympathetic ganglion which receives
inputs from preganglionic cholinergic neurons, and innervates the submandibular
salivary gland to control saliva secretion. This ganglion receives input from peptidergic
afferent neurons and such input provides the physiological pathway for local reflex
control of saliva secretion.
The calcitonin gene-related peptide (CGRP) is a 37-amino-acid peptide that was
initially described to be generated by alternative splicing of calcitonin gene 6. It has
been demonstrated that CGRP causes depolarization of SMG 7. Adrenomedullin (ADM)
is a 52-amino-acid peptide originally isolated from a human pheochromocytoma 8. It is
structurally and functionally related to the CGRP, amylin peptide family 9.
Recently, it has been demonstrated that ADM is released in saliva to stimulate oral
cell proliferation and antibacterial properties 10. Moreover, submandibular gland cells
express CGRP and ADM receptors 11.
Voltage-dependent Ca2+ channels (VDCCs) serve as crucial mediators of membrane
excitability and Ca2+-dependent functions such as neurotransmitter release, enzyme