Huntington´s disease and the interaction between Ca 2+ and cAMP signaling pathways

Abstract

Caricati-Neto A, Bergantin LB. Huntington´s disease and the interaction between Ca 2+ and cAMP signaling pathways. J Pharmacol Res December-2017;1(1):17-24. Huntington disease (HD) is a neurodegenerative disease known by progressive motor, behavioral, and cognitive decline that culminates in the death. HD therapy is yet unsatisfactory. Chorea and psychiatric symptoms usually respond to pharmacotherapy. Recent advances in pathogenesis and newer biomarkers have promoted some progresses in HD therapy. It was suggested that an imbalance in the intracellular calcium (Ca 2+) homeostasis has a key role in neurodegenerative diseases. Recently, we showed that the interaction between intracellular signaling pathways mediated by Ca 2+ and cAMP (Ca 2+ /cAMP signaling interaction) plays as a key role in several cellular responses in mammalians, including neurosecretion and cell survival. Our studies showed that the pharmacological modulation of the Ca 2+ /cAMP signaling interaction by the combined use of the Ca 2+ channel blockers (CCB), and drugs that increase the intracellular concentration of cAMP (cAMP-enhancer compounds), increases synaptic neurotransmission and stimulates neuroprotective response. Thus, we have proposed that this new pharmacological strategy could open a new avenue for the drug development more effective and safer for treatment of the neurodegenerative diseases, including HD. Here, we discuss the perspectives of the pharmacological modulation of the Ca 2+ /cAMP signaling interaction as a new therapeutic strategy for HD.

Full text

Huntington´s disease and the interaction between Ca2+ and cAMP signaling
pathways
Caricati-Neto A, Bergantin LB
Caricati-Neto A, Bergantin LB. Huntington´s disease and the interaction
between Ca2+ and cAMP signaling pathways. J Pharmacol Res
December-2017;1(1):17-24.
Huntington disease (HD) is a neurodegenerative disease known by
progressive motor, behavioral, and cognitive decline that culminates in the
death. HD therapy is yet unsatisfactory. Chorea and psychiatric symptoms
usually respond to pharmacotherapy. Recent advances in pathogenesis and
newer biomarkers have promoted some progresses in HD therapy. It was
suggested that an imbalance in the intracellular calcium (Ca2+)
homeostasis has a key role in neurodegenerative diseases. Recently, we
showed that the interaction between intracellular signaling pathways
mediated by Ca2+ and cAMP (Ca2+/cAMP signaling interaction) plays as a
key role in several cellular responses in mammalians, including
neurosecretion and cell survival. Our studies showed that the
pharmacological modulation of the Ca2+/cAMP signaling interaction by
the combined use of the Ca2+ channel blockers (CCB), and drugs that
increase the intracellular concentration of cAMP (cAMP-enhancer
compounds), increases synaptic neurotransmission and stimulates
neuroprotective response. Thus, we have proposed that this new
pharmacological strategy could open a new avenue for the drug
development more effective and safer for treatment of the
neurodegenerative diseases, including HD. Here, we discuss the
perspectives of the pharmacological modulation of the Ca2+/cAMP
signaling interaction as a new therapeutic strategy for HD.
Key Words: Ca2+/cAMP signaling interaction; Huntington´s diseases;
Neurodegenerative disease
INTRODUCTION
General aspects of Huntington's disease
Described in 1872 by american physician George Huntington, the
Huntington's disease (HD), also known as Huntington's chorea, is a
progressive and fatal neurodegenerative disorder [1]. In the world, the HD
prevalence was estimated in 5 to 10 cases per 100,000 persons [2]. The
initial physical HD symptoms are jerky, random, and uncontrollable
movements defined as chorea [1] The earliest symptoms are characterized
by alterations of mood and cognitive abilities [1]. With the disease
advance, the uncoordinated body movements become more apparent and
cognitive abilities decline into dementia [1-3]. HD symptoms can start at
any age, but generally begin between 30 and 50-year-old [1-3]. Some HD
cases start before the age of 20 years (about 8%) with symptoms similar
to Parkinson's disease [1]. The most common complications that reduce
life expectancy are lung (pneumonia) and cardiac diseases [1]. In general,
the death due to HD occurs after 15 to 20 years from initial HD symptoms
[1].
Although the precise causes of HD are not totally unknown, has been
proposed that this neurodegenerative disease is resultant from autosomal
dominant mutation of Huntingtin (HTT) gene [1,3,4]. The HTT gene
control the genetic expression of HTT protein [1,3,4]. This protein
interacts with over 100 other proteins, and appears to have multiple
biological functions [5]. Studies in animals genetically modified to exhibit
HD showed that HTT protein is involved in embryonic development, and
its absence is related to embryonic death [3,4]. Other studies indicated that
the HTT protein participates in neurotransmitter vesicular transport,
facilitating synaptic neurotransmission [6]. HTT protein is expressed in all
mammalian cells, but its function in human cells is poorly known.
Although the behavior of the mutant HTT (mHTT) protein is not fully
understood, some studies showed that mHHT is toxic to certain cell types,
particularly in the brain neurons [5]. In HD patients, the brain damage
likely related to mHTT protein was most evident in the striatum [5].
However, other brain areas are affected with the disease advance [5].
Initial HD symptoms appear related to abnormal function of the striatum
and its cortical connections [3]. The pathways by which mHTT gene may
cause neuronal death include: (1) effects on chaperone proteins; (2)
interactions with caspases (apoptotic proteins); (3) the toxic effects of
glutamine on neuronal cells; (4) impairment of energy production within
cells; and (5) effects on the expression of genes [3,4,7].
If the expression of HTT protein is increased and more HTT produced,
brain survival is improved and the effects of mHTT gene are reduced,
whereas when the expression of HTT is reduced, the resulting
characteristics are more typical of the presence of mHTT [6]. It was
showed that the disruption of the normal HTT gene does not cause the HD
in humans, but a gain of toxic function of mHTT appears to be related to
HD [3]. Thus, the detection of mHTT gene has been used as a biomarker
for the HD diagnosis in humans [8]. Although the HD represents the major
medical, social, financial and scientific problem, only symptomatic relief
drugs are available. Chorea and psychiatric symptoms usually respond to
pharmacotherapy and can improve quality of life. Actually,the therapeutic
strategies can be grouped into three categories: (1) reduction of the mHTT
protein levels; (2) improvement of the neuronal survival; and (3)
replacement of the death neurons using stem cells therapy [3,6]. Although
several pharmacological agents have been used to treat HD symptoms,
such as creatine, riluzole, dimebon, phenylbutyrate minocycline, ethyl-
EPA, coenzyme Q10, these agentes have been ineffective to prevent or
slow progression of HD in humans [1]. Tetrabenazine and benzodiazepines
have showed satisfactory results in HD patients to attenuate the motor
dysfunctions and chorea, respectively [1]. Serotonin reuptake inhibitors
and mirtazapine have been used to treat depression in HD patients, while
atypical antipsychotic drugs are used to treat psychosis and behavioral
disturbances [1]. The antiparkinson drugs have been used to treat
hypokinesia and rigidity [1].
Although the primary dysfunctions that lead to neurodegeneration and
neuronal death in the brain of HD patients are not fully understood, recent
evidences indicate that an imbalance in the intracellular calcium (Ca2+)
homeostasis in neuronal cells is directly involved in neurodegenerative
process that cause motor and cognitive dysfunctions [9,10]. It is important
REVIEW ARTICLE
Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Brazil
Correspondence: Leandro Bueno Bergantin, Laboratory of Autonomic and Cardiovascular Pharmacology, Department of Pharmacology, Escola
Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo, 669 – Vila Clementino, São Paulo-SP, Brazil, Telephone 55
11 5576-4973, e-mail leanbio39@yahoo.com.br
Received: September 07, 2017, Accepted: September 22, 2017, Published: September 26, 2017
This open-access article is distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC) (http://
creativecommons.org/licenses/by-nc/4.0/), which permits reuse, distribution and reproduction of the article, provided that the original work is
properly cited and the reuse is restricted to noncommercial purposes. For commercial reuse, contact reprints@pulsus.com
J Pharmacol Res Vol.1 No.1 December-2017 17

to note that the Ca2+ is an intracellular messenger involved in the
regulation of the multiple cellular processes, including cell proliferation
and differentiation, neurotransmitter release, hormone secretion, cell
excitation and plasticity, and others [11-19]. However, an imbalance in the
intracellular Ca2+ homeostasis could result in loss of cellular function and
death due to cytosolic Ca2+ overload [9,10]. Several studies have showed
that various neurodegenerative disorders are related to imbalance in the
intracellular Ca2+ homeostasis, including Alzheimer´s (AD) and Parkinson
´s (PD) diseases [9,10]. Thus, the use of pharmacological agents to
attenuate the neuronal cytosolic Ca2+ overload and stimulate cellular
survival mechanisms has become the major focus of the therapeutic
strategy in various neurodegenerative diseases, including HD.
Neurons are excitable cells that require extremely precise spatial-temporal
control of Ca2+-dependent processes because this ion regulates vital
functions as synaptic plasticity. When these cells are depolarized, the Ca2+
from the extracellular fluid enters into cytosol by the voltage-activated
Ca2+ channels (VACC), transiently increasing the cytosolic Ca2+
concentration ([Ca2+]c [11-19]. The nervous system expresses VACC with
unique cellular and subcellular distribution and specific functions. N-,
P/Q- and L-type VACC are distributed at neuronal cells regulating
neuronal excitability, neurotransmitter release, and gene expression
[11-19]. Evidences obtained from natural mutants, knockout mice, and
human genetic disorders indicate a fundamental role of some VACC in a
wide variety of neurodegenerative disorders, including AD and PD
[11-19]. In addition to Ca2+, other intracellular messengers participate in
the regulation of cellular functions, including 3′-5′-cyclic adenosine
monophosphate (cAMP). cAMP regulates key cellular responses,
including central metabolic events, cell growth, survival and
differentiation, secretory processes, as well as inflammatory responses
[11-19]. Due to importance of the cAMP in the cellular function, it is not
surprising that pharmacological manipulation of the cytosolic cAMP
concentration ([cAMP]c) and intracellular cAMP signaling has proven
therapeutic benefit in various human diseases. Thus, drugs that produce
the increase of [cAMP]c (cAMP-enhancer compounds) have proven
therapeutic benefit for diseases ranging from depression to inflammation
[11-19].
The efforts to understand the intracellular signaling mediated by cAMP
led to the discovery of exchange protein directly activated by cAMP
(EPAC) proteins. EPACs are specific guanine nucleotide exchange factors
for the Ras GTPase homologues, Rap1 and Rap2, which they activate
independently of the classical routes for cAMP signalling, cyclic
nucleotide-gated ion channels and protein kinase A (PKA) [11-19].
Rather, EPAC activation is triggered by internal conformational changes
induced by direct interaction with cAMP. Leading from this has been the
development of EPAC-specific agonists, which has helped to delineate
numerous cellular actions of cAMP that rely on subsequent activation of
EPAC, including the regulation of exocytosis, cell adhesion, growth,
division and differentiation.
Our previous studies have indicated that the functional interaction
between intracellular signaling pathways mediated by Ca2+ and cAMP
(Ca2+/cAMP signaling interaction) participates in several cellular
responses, including neurotransmitter/hormone exocytosis, and neuronal
survival [11-19]. These studies have also indicated that the
pharmacological modulation of the Ca2+/cAMP signaling interaction by
the combined use of the Ca2+ channel blockers (CCB) and cAMP-
enhancer compounds, such as phosphodiesterase (PDE) inhibitors, can
increase neurotransmission and additionally stimulate neuroprotective
response [11-19]. This pharmacological strategy could open a new avenue
for the drug development more effective and safer for treatment of the
neurodegenerative diseases, including HD.
Pharmacological modulation of the Ca2+/cAMP
signaling interaction as a new therapeutic strategy for
the neurodegenerative diseases
For understanding the role of the Ca2+/cAMP signaling interaction in the
regulation of the neuronal activity initially proposed by [11-19], we should
return to the past. In the 1970s, it was demonstrated that a transient
increase in the [Ca2+]c is a fundamental requirement to trigger the
neurotransmitter release [20]. In the 1980´s, the in vitro studies made by
Nobel laureate Erwin Neher using electrophysiological techniques showed
the unquestionable direct relationship between neurotransmitter release
and elevation in [Ca2+]c [21]. This relationship has become more evident
when was observed that the CCB in concentration above 1 μmol/L
inhibited the neurotransmitter release due to blockade of the VACC and
consequent reduction in the Ca2+ influx in neuronal cells.
Interestingly, some in vitro studies performed between 1975 and 1987
have demonstrated that the CCB, such as verapamil and nifedipine,
produced paradoxical sympathetic hyperactivity in concentrations below 1
μmol/L [22-24]. In accordance to these in vitro studies, several clinical
studies reported that the CCB, currently used in the antihypertensive
therapy, alleviated systemic arterial hypertension due to vasodilation
caused by the blockade of the Ca2+ influx through L-type VACC in
smooth cells of the resistance arteries, but produced tachycardia and
increase of catecholamine serum levels, characterizing CCB-induced
sympathetic hyperactivity [25]. Despite these adverse effects of CCB have
been initially attributed to adjust reflex of arterial pressure, during almost
four decades the molecular mechanism involved in these paradoxical
CCB-effects remained unclear for decades.
Using a smooth muscle richly innervated by sympathetic nerves (rat vas
deferens) as study model of the sympathetic neurotransmission, we
discovered that contractile responses mediated by sympathetic neurons
were completely abolished by L-type CCB in concentrations above 1
μmol/L due to selective and effective blockade of the Ca2+ influx through
L-type VACC in smooth cells of the vas deferens, but were paradoxically
increased in concentrations below 1 μmol/L, confirming in vitro CCB-
induced sympathetic hyperactivity [26]. Interestingly, we observed that
this CCB-induced sympathetic hyperactivity was significantly potentiated
by cAMP-enhancer compounds, such as PDE inhibitor (rolipram and
IBMX) and AC activators (forskolin) [26].
Evidences obtained since 1980´s suggested that the increase of [cAMP]c
enhances neurotransmitter release at several synapses in autonomic
nervous system of mammalians [27], reinforcing the participation of
cAMP in the neurotransmitter release. Our demonstration that CCB-
induced sympathetic hyperactivity was significantly potentiated by
cAMP-enhancer compounds was decisive to discovery that the functional
Ca2+/cAMP signaling interaction) is involved in several cellular responses
in mammalians cells, including the regulation of transmitter release from
neurons and neuroendocrine cells [11,26]. Our findings clearly
demonstrated that this paradoxical sympathetic hyperactivity results from
the augmentation of transmitter release from sympathetic neurons
produced by L-type CCB due to its interfering on the Ca2+/cAMP
signaling interaction [11-19].
This nowadays accepted concept assumes that the Ca2+/cAMP signaling
interaction virtually exist in all mammalian cells, regulated by adenylyl
cyclases (AC) and PDE [11-19]. Indeed, Ca2+ channels regulated by
ryanodine receptors (RyR) located in endoplasmic reticulum (ER) have
particularly been a forefront for the Ca2+/cAMP signaling interaction field
[11]. We discovered that in low concentration, the L-type CCB produces
moderate blockade of the L-type VACC that reduce Ca2+ influx and
[Ca2+]c, that in turn attenuate inhibitory action of Ca2+ on the AC and
increase the [cAMP]c synthesis, stimulating the intracellular signaling
pathways mediated by cAMP [11-19]. This Ca2+/cAMP signaling
interaction stimulates Ca2+ release from ER that increases
neurotransmitter release facilitating neurotransmission in sympathetic
synapses [11-19]. Some evidences have suggested that increase of
[cAMP]c reduces neuronal death triggered by cytosolic Ca2+ overload due
to stimulation of the cellular survival pathways mediated by cAMP/PKA/
CREB [28,29]. Then, a new pharmacological goal for increasing
neurotransmission in neurodegenerative diseases resulting of
neurotransmitter release deficit, and neuronal death, could be achieved by
the pharmacological modulation of the Ca2+/cAMP signaling interaction
[11-19]. We have proposed that the combined use of the L-type CCB,
prescribed in the antihypertensive therapy such as nifedipine analogous,
Caricati-Neto et al
18 J Pharmacol Res Vol.1 No.1 December-2017

and cAMP-enhancer compounds, prescribed in the antidepressive therapy
such as rolipram, could be useful to achieve this purpose.
It is important to note that the effect of this combined therapy in
attenuating neuronal death may be related to the genomic response, as
synaptic release may be attributed to a rapid response. Indeed,
pharmacological modulation of the Ca2+/cAMP signaling interaction by
combination of the L-type CCB, and cAMP-enhancer compounds, could
increase neurotransmission [11-19]. In addition, pharmacological
modulation of this interaction could subsidize the reducing of neuronal
death due to attenuation of cytosolic Ca2+ overload, increase of [cAMP]c,
and stimulation of cell survival pathways mediated by genomic response
due to activation of cellular survival pathways regulated by cAMP/PKA/
CREB-dependent intracellular signaling pathway [9,10,30]. Figure 1
illustrates how the pharmacological modulation of the Ca2+/cAMP
signaling interaction could produce the increase of neurotransmitter
release (rapid response), and the attenuation of neuronal death (genomic
response) in neurodegenerative diseases.
Figure 1: Increase of the neurotransmitter release and attenuation of
neuronal death due to pharmacological modulation of the Ca2+/cAMP
signaling interaction. The moderate inhibition by L-type CCB of the
Ca2+ influx through L-type voltage-activated Ca2+ channels (VACC)
increases the adenylyl cyclase (AC) activity and consequently
[cAMP]c. These CCB-effects can be potentiated by cAMP-enhancer
compounds (like PDE inhibitors). The combined use of the CCB with
cAMP-enhancer compounds could be useful to attenuate the motor and
cognitive dysfunctions related to HD [11-19]. PDE -
Phosphodiesterase’s, RyR - Ryanodine receptors, IP3R - IP3 receptors,
SERCA - Sarcoendoplasmic reticulum Ca2+-ATPase.
Therapeutic perspectives of the pharmacological
modulation of the Ca2+/cAMP signaling interaction in
Huntington´s disease
The development of new effective therapeutic strategies for HD depends
on the advancement of scientific knowledge about the primary
mechanisms involved in HD pathogenesis. This can take many years and
cost many millions of dollars. Thus, alternative proposal for the treatment
of HD symptoms could be attempted. In fact, some studies demonstrated
that the use of L-type CCB reduces motor and cognitive symptoms in
neurodegenerative diseases, such as AD and PD [9,10]. Studies made in
animal model of PD strongly suggest that the treatment with the L-type
CCB can reduce the progressive neuronal death due to its neuroprotective
action [9]. It is important to note that a 1-decade study involving
thousands senile hypertensive patients showed that the treatment with L-
type CCB reduced arterial pressure, and risk of dementia these patients,
indicating that this pharmacological strategy could be clinically used to
treat neurodegenerative diseases [10]. These neuroprotective effects of
CCB have been reinvestigated in thousands elderly hypertensive patients
with memory deficit [30]. These studies concluded that patients treated
with CCB had their risk of cognitive deficit decreased [30]. These
findings reinforce the idea that the attenuation of cytosolic Ca2+ overload
due to blockade of Ca2+ influx though L-type VACC blockade by L-type
CCB associated to increment of [cAMP]c could be a new pharmacological
strategy to reduce, or prevent, neuronal death in neurodegenerative
diseases [11-19].
Like PD, the HD is a neurological disease resulting from
neurodegenerative disorders that affect the motor control of skeletal
muscles, producing the progressive loss of motor function [1]. It is caused
by death of motor neurons. The loss of these neurons leads to weakness
and wasting, atrophy, of muscles used for activities such as crawling,
walking, sitting up, and controlling of head movement [1]. In severe cases
of HD, the muscles involved in breathing and swallowing are dramatically
affected. Deranged cellular signaling provides several tractable targets, but
specificity and complexity are challenges. Thus, the preservation of
neurotrophic support in HD remains a key potential therapeutic approach.
Neuronal dysfunction that affects the synaptic plasticity had been pointed
out as one of the reversible causes of motor and cognitive deficit in HD.
The use of the PDE inhibitors to restore neuronal function due to
increment of the [cAMP]c, has progressed rapidly to human trials.
Impairment of cAMP intracellular signaling and dysregulation of gene
transcription mediated by the CREB are established features of HD
[31,32]. The 10A-subtype PDE (PDE10A) is almost exclusively expressed
in the striatum, and its activity is intimately linked to the synaptic biology
of medium spiny neurons whose death is a prominent feature of HD [33].
This PDE regulates the intracellular signaling mediated by cAMP and
cyclic guanosine monophosphate (cGMP) and other neuronal responses,
including the synaptic plasticity and the response to cortical stimulation
[34,35]. The inhibition or genetic deletion of the PDE10A induces various
CREB–related gene expression changes and alterations in synaptic
function, suggested that PDE10A inhibition could be beneficial in HD
[35-37]. In fact, studies of the effects of PDE10A inhibition with TP-10 in
the R6/2 mouse have showed the ameliorated motor deficits, reduced
striatal atrophy and increased brain-derived neurotrophic factor (BDNF)
levels [38]. One concern is that early death of striatal neurons might
deplete PDE10A levels to the extent that the target is lost. However,
clinical studies using PET imaging with the specific radioligand of
PDE10A [18F]-MNI-695 suggests that PDE10A levels are sufficient even
in manifest HD to expect a meaningful response [39]. Clinical studies
using pharmacological inhibitors of PDE10A in HD patients are already
underway, with motor and functional MRI endpoints [40]. Studies using
R6/2 mouse showed that selective PDE4 inhibition with rolipram,
meanwhile, improved survival and ameliorated neuropathology and motor
phenotypes [41]. These findings reinforced the idea that the
pharmacological modulation of the Ca2+ cAMP signaling interaction by
combined use of the CCB and PDE inhibitor could be useful to attenuate
the motor and cognitive deficit in HD [11-19].
CONCLUSION
Our studies have proposed that the pharmacological modulation of Ca2+/
cAMP signaling interaction by combined use of the CCB and cAMP-
enhancer compounds could open a new avenue for the drug development
more effective and safer for treating neurodegenerative diseases, including
HD.
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