Emerging Concepts for Neuroscience Field from Ca2+/ cAMP Signalling Interaction

Abstract

The interaction between intracellular signalling pathways mediated by Ca2+
and cAMP (Ca2+/cAMP signalling interaction) is now well-accepted as a vital
cellular process for mammalians. In the neuroscience field, it has opened a new
avenue for the drug development more effective, and safer, for the treatment of
Alzheimer´s and neurodegenerative diseases. It has been almost 4 years since we
revealed the involvement of the Ca2+/cAMP signalling interaction in the enigma
of the so-called “calcium paradox”. Interestingly, the “calcium paradox” initiated
decades ago, when numerous clinical studies have reported that prescription of
L-type Ca2+ channel blockers (CCBs) for hypertensive patients decreased arterial
pressure, but produced typical symptoms of sympathetic hyperactivity. Despite
these adverse effects of CCBs have been initially attributed to adjust reflex of
arterial pressure, during almost four decades this enigmatic phenomenon (the socalled
“calcium paradox”) remained unclear. In 2013, through creative experiments,
we discovered that this phenomenon was resulting of increment of transmitter
release from sympathetic neurons, and adrenal chromaffin cells, stimulated by
CCBs due to its interference on the Ca2+/cAMP signalling interaction. Thus,
pharmacological handling of the Ca2+/cAMP signalling interaction could be a
more efficient and safer therapeutic strategy for stimulating neurotransmission
compromised by neurotransmitter release deficit, and attenuating neuronal death.

Full text

Bergantin and Caricati-Neto.
29
Emerging Concepts for Neuroscience Field from Ca2+/
cAMP Signalling Interaction
Mini-review Open Access
https://dx.doi.org/10.17756/jnen.2017-024
Leandro Bueno Bergantin* and Afonso Caricati-Neto
Laboratory of Autonomic and Cardiovascular Pharmacology, Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), 55
11 5576-4973, Rua Pedro de Toledo, 669 – Vila Clementino, São Paulo – SP, CEP: 04039-032, Brazil
*Correspondence to:
Leandro Bueno Bergantin, PhD
Laboratory of Autonomic and Cardiovascular
Pharmacology, Department of Pharmacology
Escola Paulista de Medicina, Universidade
Federal de São Paulo (UNIFESP)
55 11 5576-4973, Rua Pedro de Toledo
669 – Vila Clementino, São Paulo – SP, Brazil
E-mail: leanbio39@yahoo.com.br
Received: March 20, 2017
Accepted: May 10, 2017
Published: May 12, 2017
Citation: Bergantin LB, Caricati-Neto A. 2017.
Emerging Concepts for Neuroscience Field from
Ca2+/cAMP Signalling Interaction. J Neurol Exp
Neurosci 3(1): 29-32.
Copyright: © 2017 Bergantin and Caricati-Neto.
is is an Open Access article distributed under
the terms of the Creative Commons Attribution
4.0 International License (CC-BY) (http://
creativecommons.org/licenses/by/4.0/) which
permits commercial use, including reproduction,
adaptation, and distribution of the article provided
the original author and source are credited.
Published by United Scientic Group
Abstract
e interaction between intracellular signalling pathways mediated by Ca2+
and cAMP (Ca2+/cAMP signalling interaction) is now well-accepted as a vital
cellular process for mammalians. In the neuroscience eld, it has opened a new
avenue for the drug development more eective, and safer, for the treatment of
Alzheimer´s and neurodegenerative diseases. It has been almost 4 years since we
revealed the involvement of the Ca2+/cAMP signalling interaction in the enigma
of the so-called “calcium paradox”. Interestingly, the “calcium paradox” initiated
decades ago, when numerous clinical studies have reported that prescription of
L-type Ca2+ channel blockers (CCBs) for hypertensive patients decreased arterial
pressure, but produced typical symptoms of sympathetic hyperactivity. Despite
these adverse eects of CCBs have been initially attributed to adjust reex of
arterial pressure, during almost four decades this enigmatic phenomenon (the so-
called “calcium paradox”) remained unclear. In 2013, through creative experiments,
we discovered that this phenomenon was resulting of increment of transmitter
release from sympathetic neurons, and adrenal chroman cells, stimulated by
CCBs due to its interference on the Ca2+/cAMP signalling interaction. us,
pharmacological handling of the Ca2+/cAMP signalling interaction could be a
more ecient and safer therapeutic strategy for stimulating neurotransmission
compromised by neurotransmitter release decit, and attenuating neuronal death.
Keywords
Ca2+/cAMP signalling interaction, “Calcium paradox”, Neuroscience eld
Introduction
Nowadays, the interaction between intracellular signalling pathways mediated
by Ca2+ and cAMP (Ca2+/cAMP signalling interaction) is well-recognized as a
vital cellular process for mammalians. is interaction has opened a novel pathway
for the drug development more eective, and safer, to treating diseases related to
the neuroscience eld, such as Alzheimer´s and other neurodegenerative diseases.
e results which demonstrated the involvement of the Ca2+/cAMP signalling
interaction in the enigma of the so-called “calcium paradox” have completed a
4-years anniversary. For understanding the “calcium paradox”, we should return
to the past. Indeed, the stimulus-secretion concept to describe neurotransmitters,
and hormones, release has been resulted from ingenious experiments performed
by Douglas and Rubin in the 1960s [1]. From their concepts, in 1970´s Baker
and Knight revealed that an increase in the cytosolic Ca2+ concentration ([Ca2+]c)
is a fundamental requirement to start transmitter release [2]. In addition, the
irrefutable demonstration of a direct relationship between neurotransmitter release
and elevation in [Ca2+]c derived from the fundamental experiments performed
Journal of
Neurology & Experimental Neuroscience

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Emerging Concepts for Neuroscience Field from Ca2+/cAMP Signalling Interaction Bergantin and Caricati-Neto.
content of transmitter in the secretory vesicles (please see
gure 1) and enhancing of rate of transmitter release. us, by
elevating cAMP levels, this second messenger may enhance
the release of Ca2+ from ER. Indeed, Ca2+ is crucial for the
transmitter release, participating in virtually all the previous
mentioned processes: content of transmitter in the secretory
vesicles and rate of transmitter release. Figure 1 shows how
the pharmacological modulation of the Ca2+/cAMP signalling
interaction could produce increase of neurotransmitter release.
Indeed, many reports have shown that increase of cytosolic
cAMP concentration ([cAMP]c) stimulates neuroprotective
eects [13, 14]. us, elevating [cAMP]c by handling
Ca2+/cAMP signalling interaction could reduce neuronal
death triggered by cytosolic Ca2+ overload [8-11]. en, the
pharmacological handling of the Ca2+/cAMP signalling
interaction produced by combination of the L-type CCBs
prescribed in the antihypertensive therapy, and [cAMP]
c-enhancer compounds prescribed in the anti-depressive
therapy such as rolipram, could be a novel pharmacological
strategy for enhancing neurotransmission in neurological, and
psychiatric disorders, resulting of neurotransmitter release
decit, and neuronal death [8-11]. Figure 1 shows how the
pharmacological modulation of the Ca2+/cAMP signalling
by the Nobel laureate Erwin Neher [3]. us, by reducing
extracellular Ca2+ through blocking Ca2+ channels, we should
have a reducing in the neurotransmitter release. However,
many studies have showed that L-type Ca2+ channel blockers
(CCBs), in concentrations below 1 μmol/L, could induce
neurotransmitter release, a “paradox” [4-6]. In addition, many
results have shown that cAMP increases neurotransmitter
release at many synapses in autonomic nervous system of
vertebrate, including sympathetic neurons [7]. We recently
showed that Ca2+/cAMP signalling interaction participates
in the regulation of transmitters release from sympathetic
neurons, and adrenal chroman cells [8-11].
e Ca2+/cAMP signalling interaction as a universal concept
e Ca2+/cAMP signalling interaction is well-recognized
as a vital cellular process for mammalians. is nowadays
accepted concept assumes that these signalling pathways
virtually exist in all mammalian cells, regulated by adenylyl
cyclases (ACs) and phosphodiesterases (PDEs) [8-11]. Indeed,
endoplasmic reticulum (ER) Ca2+ channels have particularly
been a forefront for the Ca2+/cAMP signalling interaction
eld, such as ryanodine receptors (RyR) [8-11]. We established
that Ca2+/cAMP signalling interaction plays a fundamental
participation in the regulation of neurotransmitter release
from neurons and neuroendocrine cells [8-11]. en, Ca2+/
cAMP signalling interaction could be a novel therapeutic
target for medicines.
e Ca2+/cAMP signalling interaction and the neuroscience
eld
Several medical studies have been evidencing that
prescription of L-type CCBs in the antihypertensive
pharmacotherapy decreased arterial pressure arterial,
but produced typical clinical symptoms of sympathetic
hyperactivity [12]. Despite these adverse eects of CCBs have
been initially attributed to adjust reex of arterial pressure,
during almost four decades this enigmatic phenomenon named
“calcium paradox” remained without additional explanation.
In 2013, through creative experiments, we discovered that the
“calcium paradox” phenomenon was resulting of increment
of transmitter release from sympathetic neurons, and adrenal
chroman cells, stimulated by CCBs due to its interference
on the Ca2+/cAMP signalling interaction [9]. We showed that
sympathetic-mediated contractions of the vas deferens were
completely inhibited by L-type CCBs in high concentrations
(>1 μmol/L), but unpredictably, and paradoxically, potentiated
in concentrations below 1 μmol/L, characterized by CCBs-
induced sympathetic hyperactivity [4-6, 9]. Our studies
showed that this hyperactivity is caused by increment of
neurotransmitter release from sympathetic neurons produced
by L-type CCBs due to its interference on the Ca2+/cAMP
signalling interaction [8-11]. Briey, the reduction of Ca2+
inux through L-type voltage-activated Ca2+ channels
produced by CCBs enhances the adenylyl cyclase activity
(and consequently elevating cAMP levels, please see gure 1).
ese CCBs-eects can be potentiated by cAMP-enhancer
compounds (like PDEs inhibitors). In fact, the fundamental
mechanisms by which Ca2+/cAMP signalling interaction
may increase the transmitter release are due: increasing of
Figure 1: Increase of neurotransmitter release and attenuation of neuronal
death triggered by cytosolic Ca2+ overload by means pharmacological
modulation of the Ca2+/cAMP signalling interaction. e reduction of Ca2+
inux through L-type voltage-activated Ca2+ channels produced by CCBs
enhances the adenylyl cyclase activity (and consequently cAMP). ese
CCBs-eects can be potentiated by cAMP-enhancer compounds (like
PDEs inhibitors). PDEs - Phosphodiesterases, RyR - Ryanodine receptors,
IP3R - IP3 receptors, SERCA - Sarcoendoplasmic reticulum Ca2+-ATPase.

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Emerging Concepts for Neuroscience Field from Ca2+/cAMP Signalling Interaction Bergantin and Caricati-Neto.
interaction could produce attenuation of neuronal death.
In fact, it was showed that the prescription of L-type CCBs
reduces motor symptoms, and reduces progressive neuronal
death in animal model of Parkinson´s disease, suggesting
that L-type CCBs are potentially viable neuroprotective
pharmaceuticals [15]. Additionally, a 1-decade follow-up
study (2000 to 2010), involving 82,107 hypertensive patients
of more than 60 years of age, demonstrated that prescription
of L-type CCBs during antihypertensive therapy reduces
risk of dementia in these patients, indicating that these
pharmaceuticals could be clinically used to treat Alzheimer´s
disease [16]. ese ndings for the neuroprotective CCBs-
eects have been demonstrated in 1,241 elderly hypertensive
patients with memory impairment [17]. e prescription
of CCBs decreased the risk of cognitive impairment, and
Alzheimer´s disease, independently of blood pressure levels
when compared to patients not receiving CCBs [17]. ese
ndings highlight the concept that attenuation of cytosolic
Ca2+ overload produced by L-type CCBs due to blockade
of Ca2+ inux could be a successful pharmacological strategy
to reduce, or prevent, neuronal death in neurodegenerative
diseases. Finally, these ndings could open a new way for
the drug development more eective, and safer, for the
pharmacotherapy of Alzheimer´s and other neurodegenerative
diseases [18-24].
Conclusion
is work proposes that pharmacological interference
on the Ca2+/cAMP signalling interaction could be a more
ecient, and safer, therapeutic strategy for stimulating
neurotransmission compromised by neurotransmitter release
decit, and reducing neuronal death.
Disclosure Statement
Caricati-Neto and Bergantin thank the continued
nancial support from CAPES, CNPq and FAPESP
(Bergantin´s Postdoctoral Fellowship FAPESP #2014/10274-
3). e authors also thank Elsevier - “author use”: Reuse of
portions or extracts from the article in other works - https://
www.elsevier.com/__data/assets/pdf_file/0007/55654/
AuthorUserRights.pdf
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