Accepted Manuscript

Calcium signaling in health, disease and therapy

Jan B. Parys, Geert Bultynck

PII: S0167-4889(18)30313-6
DOI: doi:10.1016/j.bbamcr.2018.08.019
Reference: BBAMCR 18352
To appear in: BBA - Molecular Cell Research

Please cite this article as: Jan B. Parys, Geert Bultynck , Calcium signaling in health,
disease and therapy. Bbamcr (2018), doi:10.1016/j.bbamcr.2018.08.019

This is a PDF file of an unedited manuscript that has been accepted for publication. As
a service to our customers we are providing this early version of the manuscript. The
manuscript will undergo copyediting, typesetting, and review of the resulting proof before
it is published in its final form. Please note that during the production process errors may
be discovered which could affect the content, and all legal disclaimers that apply to the
journal pertain.
 ACCEPTED MANUSCRIPT

Preface

Calcium signaling in health, disease and therapy

Most molecular players controlling intracellular Ca2+ handling and signaling, the so-called Ca2+-signaling
toolkit, have been identified and characterized in the previous decades [1]. The interplay between these
various Ca2+ channels, pumps and exchangers not only maintains basal cellular Ca2+ homeostasis but also
enables the dynamic and tightly controlled change of cytosolic or organellar [Ca2+]. These intracellular
Ca2+ signals can be limited to specific intracellular locations, establishing Ca2+ microdomains, or be

PT
global, thereby impacting the complete cell, or even be propagated towards functionally coupled,
neighboring cells. These different types of Ca2+ signals are instrumental in regulating a plethora of

RI
physiological processes at the cellular level. These processes, critical for human health, include
fertilization, metabolism, secretion, muscle contraction, gene activation, cell proliferation, cell death,
autophagy, etc.

SC
Originally, the number of diseases linked to aberrant Ca2+ handling was relatively small, and often
related to cardiac or skeletal muscle malfunction. Yet, more recent research clearly underscored the
NU
relevance of Ca2+ signals for the proper function of a broad spectrum of cell types and organs in the
human body. Furthermore, recent advances in our understanding of the complex regulation of
intracellular [Ca2+] reveal that even subtle alterations and disturbances in the Ca2+-handling and Ca2+-
transport systems can severely impact Ca2+ signaling, causing the dysfunction of cells, tissues and organs
MA

eventually resulting in illness. As such, the field continues to produce novel insights in the role of Ca2+
signaling in processes underlying human health and to provide molecular handles to tackle pathologies.
These developments will contribute to novel, improved or personalized strategies with therapeutic
D

potential. Therefore, we aspired to highlight in this Special Issue of Biochimica Biophysica Acta –
Molecular Cell Research the emerging relevance of Ca2+ signaling in health and disease and its potential
E

for developing unique and unprecedented therapeutic strategies.

PT

We have organized the articles in six thematic themes, being (i) the molecular basis of Ca2+-related
diseases, (ii) Ca2+ signaling in neuropathies, (iii) Ca2+ signaling in secretory diseases, (iv) Ca2+ signaling in
cancer therapy, (v) Ca2+ signaling in (in)fertility, and (vi) Ca2+ signaling in infection. The thematic
CE

organization of the topics covered in this Special Issue is displayed in Fig. 1.

(i) The first set of articles in this issue covers the contribution and role of Ca2+-binding proteins, Ca2+-
transporting proteins or Ca2+-signaling pathways in health and disease, providing a timely view on the
AC

molecular basis of Ca2+-related diseases.

First, Boeckel and Ehrlich highlight the role of Neuronal Calcium Sensor-1 (NCS-1), a Ca2+-binding protein
related to calmodulin and especially, but not exclusively, expressed in neurons [2]. NCS-1 regulates
several signaling pathways via direct interaction with a variety of target proteins, including the inositol
1,4,5-trisphosphate (IP3) receptor (IP3R), a ubiquitously expressed intracellular Ca2+-release channel.
Interestingly, NCS-1 has been implicated in a large number of diseases, ranging from neurological
diseases to cancer, substance abuse disorders and chemotherapy-induced peripheral neuropathy.

Second, sphingolipids regulate several cellular functions by affecting many different signaling pathways.
Pulli et al. elucidate the various mechanisms by which sphingolipids such as sphingosine and
sphingosine 1-phosphate can modulate Ca2+ signaling and thus impact cellular function with
pathophysiological consequences [3]. This includes effects on almost all members of the Ca2+-signaling
toolkit but in particular store-operated Ca2+ entry (SOCE), lysosomal Ca2+ handling via the two-pore
 ACCEPTED MANUSCRIPT

channels (TPCs), transient receptor potential (TRP) channels, and the Ca2+-release channels of the sarco-
/endoplasmic reticulum (SR/ER), the IP3R and the ryanodine receptor (RyR).

Third, TPCs participate in the release of Ca2+ from the lysosomes after activation e.g. by the second
messenger NAADP. Patel and Kilpatrick discuss the role of these endolysosomal Ca2+ channels in
diseases such as Parkinson's disease, non-alcoholic fatty liver disease, Ebola infection, cancer, cardiac
dysfunction and diabetes [4]. Moreover, the paper shows how interfering with TPC activity can correct
some of these pathological conditions, providing a basis for the development of new therapeutic
approaches.

The two main intracellular Ca2+-release channels, the RyR and the IP3R, are implicated in several
pathological outcomes. Kushnir et al. discuss how RyR dysfunction leads to several disorders [5]. As

PT
RyRs are highly expressed in skeletal and cardiac muscle, its dysfunction leads to pathologies associated
with heart failure, arrhythmias and myopathies. Interestingly, its expression in other tissues as brain and

RI
pancreas can also be linked to a variety of diseases, including post-traumatic stress disorder, Alzheimer’s
disease, spinocerebellar ataxia (SCA) and diabetes, while it also can contribute to pulmonary and
immune disorders. Importantly, targeting dysregulated RyR activity can have beneficial effects. The IP3R

SC
is the subject of two distinct papers. Wang and Yule highlight how the activity of channels in general
and of the IP3R in particular can be modulated in a very specific way by proteases, such as calpains and
caspases [6]. Moreover, alterations in this mode of regulation can contribute to disease states due to
NU
Ca2+ overload such as e.g. acute pancreatitis. Kerkhofs et al. in turn provide an extensive review of the
different disease-linked mutations identified in ITPR1-3 genes that encode for the three IP3R isoforms
[7]. While mutations in the type 1 IP3R isoform lead to neurological disorders such as SCAs, mutations in
MA

type 2 and 3 are linked to secretory problems, cancer and autoimmune diseases.

(ii) The second set of articles covers the role of (dysregulated) Ca2+ signaling in neuropathies. Following
up on the role of RyRs and IP3Rs in diseased states in general and neuropathies in particular, these
articles all explore in great detail the impact of Ca2+ signaling on the occurrence of respectively autism
D

spectrum disorder (ASD), SCAs and Alzheimer’s disease. ASD forms a group of hereditary neurological
E

disorders affecting cognitive, social and verbal development caused by a combination of multiple
genetic and environmental factors, though how these factors underlie ASD remains poorly understood.
PT

Nguyen et al. focus on Ca2+ signaling as common denominator for the different pathways linked to ASD
[8]. The interplay between ASD and defects at the level of voltage-operated Ca2+ channels and IP3Rs,
including their importance for ER-to-mitochondria Ca2+ signaling, is extensively discussed. Subsequently,
CE

Hisatsune et al. concentrate on the relation between Ca2+ signaling and SCAs [9]. Various forms of SCA
relate to defects in components of the Ca2+-signaling toolkit. Hence, several types of SCA relate to
mutations in the type 1 IP3R, though other types of SCA are consequences of mutations in other proteins
AC

directly (TRPC3) or indirectly (ataxins, β-III spectrin, protein kinase C γ, metabotropic glutamate
receptor) affecting Ca2+ signaling. Finally, Tong et al. discuss how dysregulation of neuronal Ca2+
signaling underlies and contribute to the development of Alzheimer’s disease. On the one hand,
deranged Ca2+ signaling can affect the processing of amyloid precursor protein to amyloid β and the
phosphorylation of tau protein [10]. On the other hand, aging can affect the various proteins and
organelles involved in intracellular Ca2+ handling. Thus, altered ER Ca2+ handling (in particular IP3Rs and
RyRs as major Ca2+-release channels), the subsequent SOCE process, the other plasma membrane Ca2+
channels as well as lysosomal and mitochondrial Ca2+ handling have been implicated in Alzheimer’s
disease. Therefore, these Ca2+-transport systems could serve as valid therapeutic targets.

(iii) A third set of articles provide a timely account of Ca2+ signaling in secretory diseases. Since the
secretory process is highly Ca2+ dependent, it isn’t surprising that dysregulation of Ca2+ signaling will
strongly impact the function of secretory cell types and thus lead to pathological states. First, Trampert
and Nathanson give an overview of the Ca2+-signaling mechanisms in hepatocytes, especially
 ACCEPTED MANUSCRIPT

highlighting the role of IP3R2, and in cholangiocytes, especially highlighting the crucial role of IP3R3, and
explain their role in bile formation and secretion [11]. The occurrence of cholestasis consecutively to
changes in Ca2+ signaling and the possible therapeutic implications are discussed. Second, Indu
Ambudkar educates us on the role of the IP3R–SOCE pathway in salivary gland function. She further
pinpoints the role of Ca2+ signaling defects in two pathological conditions associated with an irreversible
damage to the salivary gland, i.e. radiation therapy for head-and-neck cancers and Sjögren's syndrome
[12]. Third, Eckstein et al. enlighten the reader on the role of Ca2+ signaling in enamel formation and
how Ca2+ dysregulation can lead to enamelopathies [13]. Several organellar Ca2+-transport mechanisms
are involved in the latter and include different Ca2+ channels, pumps, exchangers and buffers.

(iv) A fourth set of articles explores the therapeutic potential of targeting Ca2+-signaling systems and

PT
their accessory proteins in cancer and the contribution of Ca2+ signaling to therapeutic anti-cancer
interventions. It is clear that Ca2+ signals critically impact cellular life and death decisions [14, 15],
whereby intervening with these signals can specifically drive cancer cell demise. This is particularly

RI
interesting in the case of tumoral growth, whereby tools that manipulate the activity of Ca2+-handling
proteins can then be used in anti-cancer strategies. First, Bong and Monteith present a thorough

SC
analysis on the specific Ca2+-transporting proteins to be targeted in specific cancers, on the links
between Ca2+ signaling and cancer therapies and therapy resistance and on the role of Ca2+ signals in the
tumor microenvironment [16]. Second, Clark Distelhorst integrates earlier insights from corticosteroid-
NU
mediated cell death into innovative approaches for inducing cancer cell death in response to sustained
[Ca2+] elevations [17]. He reveals the specific possibility of targeting the IP3R at its binding site for the
anti-apoptotic protein Bcl-2, an IP3R-inhibiting protein upregulated in different types of cancers [18].
Furthermore, he illustrates in great detail how peptides that prevent Bcl-2’s inhibitory action on IP3Rs
MA

can provoke cancer cell death, underscoring the ensuing therapeutic value of this approach. Third,
Hoorelbeke et al. explore the role of Ca2+ signaling in photodynamic therapy, a clinically used anti-
cancer regimen [19]. Photodynamic therapy relies on the activation of a photosensitizer compound to
produce toxic reactive oxygen species (ROS). ROS formation affects intracellular Ca2+ handling, leading to
D

Ca2+ overload and cell death. This therapy proved to be very useful for the treatment of several cancers,
E

especially skin, lung and esophagus cancers. In addition, Ca2+ signals can arise in neighboring cells via
gap junctions and hemichannel activity, leading to bystander effects via NO and/or new ROS production.
PT

Depending on the conditions, these effects can either contribute to increased tumoral cell death or to
toxic effects for the surrounding, healthy tissue. The authors make clear that a better understanding of
the control of the bystander effects is required to improve photodynamic therapy, both in terms of
CE

efficiency and specificity.

(v) A fifth set of articles attracts the reader to the well-established role of Ca2+ signals in reproduction
AC

and (in)fertility. De Clercq and Vriens discuss the general role of Ca2+ in reproduction with a special
focus on the emerging role of TRP channels [20]. TRP channels form a large family containing in
Mammalia 28 members, divided in 6 groups. The authors explain how different TRP channel isoforms
contribute to the distinct phases of reproduction, participating not only in spermatogenesis and
oogenesis, but also in the implantation and placentation processes. However, further work will not only
be needed to fully unravel the role of TRP channels in reproduction but also to elucidate their
contribution to pathologies, such as intra-uterine growth restriction, repeated implantation failure or
pregnancy loss and preeclampsia. Karl Swann first clarifies how at fertilization phospholipase C ζ present
in sperm evokes in oocytes Ca2+ oscillations that are critical for their activation [21]. Subsequently, he
explains that Ca2+ oscillations also occur after intracytoplasmic sperm injection. In the event that the
sperm lacks functional phospholipase C ζ, Ca2+ signals can be triggered by various treatments. Yet, the
only method currently in clinical practice is the application of a Ca2+ ionophore, which however causes
non-physiological [Ca2+] elevations in the oocyte. Therefore, future treatments that mimic better the
physiological low frequency, high amplitude Ca2+ signals may yield improved outcomes.
 ACCEPTED MANUSCRIPT

(vi) Last but not least, the role of Ca2+ signaling in infection is the subject of the final two papers. Tran
Van Nhieu et al. points out how bacterial pathogens can increase their own virulence by interfering with
the intracellular Ca2+ signals in the host cells [22]. Different properties have been found for the various
bacterial toxins, which can function as Ca2+-permeable pore-forming proteins and/or proteins affecting
IP3-induced Ca2+ release. As a consequence, upon infection, Ca2+ signaling is altered at either global or
local level, influencing cell adhesion, endocytosis, inflammatory response, cell death and autophagy.
Finally, Hortua Triana et al. consider the important role of Ca2+ signaling in controlling the lytic cycle of
the protozoa Toxoplasma gondii, an intracellular parasite belonging to the phylum of the Apicomplexa
[23]. Although in the last few years progress has been realized in understanding the stimulatory action
of Ca2+ for the lytic cycle, several steps remain to be clarified. Moreover, the Ca2+-signaling toolkit
present in these parasites remains not fully understood. This is at least partly due to the evolutionary

PT
distance existing between Apicomplexa and the Mammalia, but is important to fully resolve in order to
definitively identify potential targets for pharmacological compounds.

RI
In conclusion, this set of timely and comprehensive reviews underscores the importance of Ca2+
signaling in health and disease for different models and systems. Moreover, this collection of articles

SC
also provides a framework for the future translation of this knowledge towards treating diseases and
developing novel therapeutic tools and approaches. NU
References.

[1] M.J. Berridge, M.D. Bootman, H.L. Roderick, Calcium signalling: dynamics, homeostasis and
MA

remodeling, Nat. Rev. Mol. Cell Biol. 4 (2003) 517-529.

[2] G.R. Boeckel, B.E. Ehrlich, NCS-1 is a regulator of calcium signaling in health and disease, Biochim.
Biophys. Acta (in press).
[3] I. Pulli, M.Y. Asghar, K. Kemppainen, K. Törnquist, Sphingolipid-mediated calcium signaling and its
D

pathological effects, Biochim. Biophys. Acta (in press).

[4] S. Patel, B.S. Kilpatrick, Two-pore channels and disease, Biochim. Biophys. Acta (in press).
E

[5] A. Kushnir, B. Wajsberg, A.R. Marks, Ryanodine receptor dysfunction in human disorders, Biochim.
PT

Biophys. Acta (in press).

[6] L. Wang, D.I. Yule, Differential regulation of ion channels function by proteolysis, Biochim. Biophys.
Acta (in press).
CE

[7] M. Kerkhofs, B. Seitaj, H. Ivanova, G. Monaco, G. Bultynck, J.B. Parys, Pathophysiological

consequences of isoform-specific IP3 receptor mutations, Biochim. Biophys. Acta (in press).
[8] R.L. Nguyen, Y.V. Medvedeva, T.E. Ayyagari, G. Schmunk, J.J. Gargus, Intracellular calcium
AC

dysregulation in autism spectrum disorder: An analysis of converging organelle signaling pathways,

Biochim. Biophys. Acta (in press).
[9] C. Hisatsune, K. Hamada, K. Mikoshiba, Ca2+ signaling and spinocerebellar ataxia, Biochim. Biophys.
Acta (in press).
[10] B.C.-K. Tong, A.J. Wu, M. Li, K.-H. Cheung, Calcium signaling in Alzheimer's disease & therapies,
Biochim. Biophys. Acta (in press).
[11] D.C. Trampert, M.H. Nathanson, Regulation of bile secretion by calcium signaling in health and
disease, Biochim. Biophys. Acta (in press).
[12] I. Ambudkar, Calcium signaling defects underlying salivary gland dysfunction, Biochim. Biophys. Acta
(in press).
[13] M. Eckstein, F.J. Aulestia, M.K. Nurbaeva, R.S. Lacruz, Altered Ca2+ signaling in enamelopathies.
Biochim. Biophys. Acta (in press).
[14] G. Bultynck, J.B. Parys, Ca2+ signaling and cell death: Focus on Ca2+-transport systems and their
implication in cell death and survival, Cell Calcium 69 (2018) 1-3.
 ACCEPTED MANUSCRIPT

[15] J.B. Parys, G. Bultynck, Ca2+ signaling and cell death: Focus on the role of Ca2+ signals in the
regulation of cell death & survival processes in health, disease and therapy, Cell Calcium 70 (2018) 1-2.
[16] A.H.L. Bong, G.R. Monteith, Calcium signaling and the therapeutic targeting of cancer cells, Biochim.
Biophys. Acta (in press).
[17] C.W. Distelhorst, Targeting Bcl-2-IP3 receptor interaction to treat cancer: A novel approach inspired
by nearly a century treating cancer with adrenal corticosteroid hormones, Biochim. Biophys. Acta (in
press).
[18] T. Vervliet, J.B. Parys, G. Bultynck (2016), Bcl-2 proteins and calcium signaling: complexity beneath
the surface, Oncogene 35 (2016) 5079-5092.
[19] D. Hoorelbeke, E. Decrock, V. Van Haver, M. De Bock, L. Leybaert, Calcium, a pivotal player in
photodynamic therapy?, Biochim. Biophys. Acta (in press).

PT
[20] K. De Clercq, J. Vriens, Establishing life is a calcium-dependent TRiP: Transient receptor potential
channels in reproduction, Biochim. Biophys. Acta (in press).
[21] K. Swann, The role of Ca2+ in oocyte activation during in vitro fertilization: Insights into potential

RI
therapies for rescuing failed fertilization, Biochim. Biophys. Acta (in press).
[22] G. Tran Van Nhieu, G. Dupont, L. Combettes, Ca2+ signals triggered by bacterial pathogens and

SC
microdomains, Biochim. Biophys. Acta (in press).
[23] M.A. Hortua Triana, K.M. Márquez-Nogueras, S.A. Vella, S.N.J. Moreno, Calcium signaling and the
lytic cycle of the apicomplexan parasite Toxoplasma gondii, Biochim. Biophys. Acta (in press).
NU
MA

Jan B. Parys and Geert Bultynck,

KU Leuven, Laboratory for Molecular and Cellular Signaling,
Department of Cellular and Molecular Medicine & Leuven Kanker Instituut,
D

Campus Gasthuisberg O/N-1 B-802, Herestraat 49,

BE-3000 Leuven, Belgium
E

Jan.parys@kuleuven.be and geert.bultynck@kuleuven.be

PT
CE

Caption:

Fig. 1. Schematic overview of the 6 topics covered in this Special Issue, presented in clock-wise direction:
AC

the molecular basis of Ca2+-related diseases (red), followed by the role of Ca2+ signaling in neuropathies
(blue), in secretory diseases (green), in cancer therapy (orange), in (in)fertility (purple), and in infection
(pink). At the outside, the respective themes of the different articles for each of the 6 topics are
indicated in the same colors.
 ACCEPTED MANUSCRIPT

Dr. Jan B. Parys is Professor of Physiology and Head of the Laboratory of Molecular and Cellular
Signaling at the KU Leuven (Belgium). He obtained a Master in Plant Physiology in 1980, a Master in
Medical Sciences in 1982 and a Ph.D in 1986. He was lecturer at the University of Algiers from 1986-
1990 and research associate at the Univ. of Iowa with Kevin Campbell from 1990-1992. His research
focused on the understanding of the mechanisms for Ca2+ homeostasis in general and the structure,
function and regulation of the inositol 1,4,5-trisphosphate receptor in particular. His research now
especially concerns the role of Ca2+ signaling and Ca2+ microdomains in apoptosis and autophagy. He
authored or co-authored more than 250 articles and recently edited the book “Calcium techniques, a
laboratory manual” (CSH Press) together with M.D. Bootman, D.I. Yule and G. Bultynck. Since 2010 he is
Secretary-General of the European Calcium Society (ECS), and organized or co-organized several
international workshops and meetings of the ECS.

PT
RI
SC
NU
MA
E D
PT
CE
AC
 ACCEPTED MANUSCRIPT

Dr. Geert Bultynck is a Professor in the Laboratory of Molecular and Cellular Signaling in the
Department of Cellular & Molecular Medicine, KU Leuven (Belgium) since 2008 onwards. He obtained a
Master in Biochemistry in 1997 and a PhD in Medical Sciences in 2001 at KU Leuven under guidance of
Prof. Humbert De Smedt and Prof. Jan B. Parys, working on immunophilins in Ca2+-signaling regulation.
As a postdoctoral researcher, he joined the lab of Prof. Martha Cyert (Stanford University, CA) from
2003 till 2006, studying novel calcineurin targets in yeast. His research now is focusing on exploring and
exploiting the role of intracellular Ca2+-release channels and their accessory proteins in cell death and
survival in health, disease & therapy. He authored or co-authored more than 160 articles and has been
the Guest Editor of Special Issues for BBA – Molecular Cell Research (together with Jacques Haiech, Claus
W. Heizmann, Joachim Krebs and Marc Moreau; 2013), Frontiers in Oncology (together with Cesar
Cardenas and Paolo Pinton; 2017) and Cell Calcium (together with Jan B. Parys; 2018) and of the

PT
scientific book on “Calcium techniques, a laboratory manual” for Cold Spring Harbor Press (together
with Martin D. Bootman, David I. Yule and Jan B. Parys; 2013). Currently, he serves the Editorial Board of

RI
Cell Calcium, BBA – Molecular Cell Research and Cells journals. He also coordinates an FWO-research
community on Ca2+ signaling in health, disease & therapy.

SC
NU
MA
E D
PT
CE
AC
Figure 1