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and others

Role of gill Ca2C-sensing





Activation of gill Ca2C-sensing

receptor as a protective pathway to
reduce Ca2C-induced cytotoxicity

should be addressed
to C K C Wong

J Gu, A Y S Law, B H Y Yeung and C K C Wong

Department of Biology, Croucher Institute for Environmental Sciences, Hong Kong Baptist University,
Kowloon Tong, Hong Kong, China

Journal of Molecular Endocrinology

The expression of the Ca2C-sensing receptor (Casr) in the endocrine gland known as
the corpuscle of Stannius (CS) regulates the secretion of the hypocalcemic hormone
stanniocalcin-1 (STC1) to inhibit gill Ca2C uptake. Although numerous studies have reported
the branchial expression of Casr and Stc1, the functions of these proteins in gills have not
been elucidated yet. On the basis of recent findings regarding the autocrine/paracrine
functions of STC1 in mammalian models, we proposed the hypothesis that branchial CaSR
has an in situ sensing function to regulate STC1 that maintains local Ca2C homeostasis.
In this study, we investigated Casr-mediated signaling and its regulation of Stc1 and
cyclooxygenase-2 (Cox2) expression/function using a primary gill-cell culture model.
The biochemical responses of gill cells isolated from Japanese eels to an increasing
concentration of extracellular Ca2C (0.11 mM) were tested. This stimulation led to a
transient increase in phosphatidylcholine-phospholipase C (PC-PLC) activity, followed by
activation of ERK and inositol 1,4,5-trisphosphate-Ca2C/calmodulin-dependent protein
kinase 2 (CaMK2) signaling pathways. Cotreatment with the calcimimetic R467 caused
synergistic effects on Ca2C-stimulated PC-PLC activity, ERK signaling, and CaMK2 signaling.
The activation of the CaSR-PLC-ERK pathway was associated with increased expression levels
of Stc1 and Cox2 as confirmed by the inhibition of Erk using a chemical inhibitor, PD98059.
Functionally, Ca2C/R-467 pretreatment was found to protect cells from thapsigargin-induced
cell death. Inhibition of COX2 activity using NS398 abolished this protection, while
transduction of STC1 lentiviral particles in the gill cells increased the protective effects.
Collectively, our data revealed the expression of functional CaSR in gill tissues. The
identification of the CaSR-STC1/COX2-mediated protective pathway in gill cells sheds light
on a possible cellular protective mechanism against an increase in intracellular Ca2C levels
associated with transepithelial Ca2C transport.

Key Words

calcium signaling


gene expression




cell culture

Journal of Molecular
(2014) 53, 155164

Calcium ions have a variety of beneficial roles in living
organisms. Their function is pleiotropic, ranging from
the regulation of signaling cascades in a single cell to
DOI: 10.1530/JME-14-0060

! 2014 Society for Endocrinology

Printed in Great Britain

a wide variety of physiological functions at the organ

level. Failure to maintain Ca2C homeostasis affects a
variety of molecular and cellular processes, ultimately
Published by Bioscientifica Ltd.