Impact of interaction of Ca 2+ /cAMP Intracellular Signalling Pathways in Clinical Pharmacology and Translational Medicine

Abstract

The pharmacological manipulation of interaction of the intracellular signalling pathways mediated by Ca 2+ and cAMP (Ca 2+ /cAMP interaction) may provide new insights for the pharmacotherapy of psychiatric disorders, dramatically impacting clinical pharmacology and translational medicine. Disorders mainly resulting by reduction of serotonin and catecholamine release in central nervous system could be directly impacted by the manipulation of the Ca 2+ /cAMP interaction, such as depression. Since 1975, several clinical studies have reported that administration of L-type Ca 2+ channel blockers (CCBs) produces reduction in vascular resistance and arterial pressure in hypertensive patients, associated with an increase in plasma noradrenaline levels and tachycardia characterized by sympathetic hyperactivity. During almost four decades these enigmatic phenomena remained unclear. In 2013, we discovered that this paradoxical sympathetic hyperactivity produced by CCBs is due to its interference on the Ca 2+ / cAMP interaction. Then, the pharmacological manipulation of this interaction could be a more efficient therapeutic strategy for increasing serotoninergic and monoaminergic neurotransmission in depression.

Full text

Leandro Bueno Bergantin*, and Afonso Caricati-Neto
Department of Pharmacology – Universidade Federal de São Paulo – Escola Paulista de Medicina, Laboratory of Autonomic and
Cardiovascular Pharmacology
Abstract: The pharmacological manipulation of interaction of the intracellular signalling pathways mediated by Ca2+ and cAMP
(Ca2+/cAMP interaction) may provide new insights for the pharmacotherapy of psychiatric disorders, dramatically impacting
clinical pharmacology and translational medicine. Disorders mainly resulting by reduction of serotonin and catecholamine release in
central nervous system could be directly impacted by the manipulation of the Ca2+/cAMP interaction, such as depression. Since
1975, several clinical studies have reported that administration of L-type Ca2+ channel blockers (CCBs) produces reduction in
vascular resistance and arterial pressure in hypertensive patients, associated with an increase in plasma noradrenaline levels and
tachycardia characterized by sympathetic hyperactivity. During almost four decades these enigmatic phenomena remained unclear.
In 2013, we discovered that this paradoxical sympathetic hyperactivity produced by CCBs is due to its interference on the Ca2+/
cAMP interaction. Then, the pharmacological manipulation of this interaction could be a more efficient therapeutic strategy for
increasing serotoninergic and monoaminergic neurotransmission in depression.
Impact of interaction of Ca2+/cAMP Intracellular Signalling Pathways in
Clinical Pharmacology and Translational Medicine
Case Report
Clinical Pharmacology and Translational Medicine
© All rights are reserved by Bergantin LB and Caricati N
Introduction
Depression is a psychiatric disease resulting mainly by dysfunction
of monoaminergic neurotransmission in central nervous system [1,
2]. Depression is a severe global illness, becoming more and more
common each decade. Because of specific symptoms, it is considered
as a leading cause of disability all over the world with a high death
factor due to suicides. There are many antidepressants used in the
therapy, but still more than one-third of patients do not respond to
the current therapy [2]. The heterogeneous nature of the illness and
its complex, and unclear etiology, may be responsible for treatment
difficulties. Next to the main monoaminergic hypothesis of
depression, there are also many other approaches connected with the
pathophysiology of thisdisease,including hypothalamic-pituitary-
adrenalaxis dysregulation, dopaminergic, cholinergic, glutamatergic
or GABA-ergic neurotransmission [2].
Nevertheless, it can be unambiguously stated that serotonergic,
noradrenergic and dopaminergic systems (monoaminergic
neurotransmission) are precisely associated with pathogenesis of
depression, and should be therefore considered as valuable targets in
patients' treatment. Thus, novel strategies to treat depression,
throughout our recent discovery entitled “calcium paradox” due to
interaction between the intracellular signalling pathways mediated by
Ca2+ and cAMP (Ca2+/cAMP interaction), may be an advantage
[1, 3, 4].
Current Therapy to Treat Depr ession
Depression is an incapacitating psychiatric condition that causes a
significant problem on individuals and society. There is still a lack of a
clear understanding of the neuropathological changes associated with
this illness, and the efficacy of antidepressants is still far from the best
[5,6]. Research into antidepressant therapies has derived from
observations in human trials and animal models after the first
monoaminergic hypothesis emerged (about six decades ago). However,
glutamatergic modulators, such as ketamine also have become the
forefront of antidepressant exploration, especially for treatment-
resistant depression and suicidal ideation [5, 6]. The glutamatergic
hypothesis of depression is not novel, however other NMDA receptor
modulators do not seem to share the rapid and sustained effects of
ketamine, suggesting that a unique combination of intracellular targets
might be involved in its effect [5, 7]. Interestingly, inflammation can
impact the glutamatergic system enhancing excitotoxicity and
decreasing neuroplasticity. The points of convergence between the
inflammatory and glutamatergic hypotheses of depression are not
completely established, especially regarding the effects of fast-acting
antidepressants [5, 7].
Nonetheless, the monoamine hypothesis of depression continues to
dominate the field and clinical trials, which postulates that an imbalance in
monoaminergic neurotransmission is causally related to the clinical
features of depression [6, 7]. Antidepressants influence serotonin whose
mainly goal consist at raising serotonin concentrations, thereby increasing
serotonergic transmission at the level of the synapse, for example by
inhibiting the serotonin neuronal transporter. However, the serotonin
system is multifaceted. Different serotonin receptor subtypes turn the
serotonergic system into a complex neurochemical arrangement that
influences diverse neurotransmitters in various brain regions. Classical
antidepressants, as well as other psychopharmacological agents have
various crucial effects on serotonin receptors. Researchers aim to provide a
useful characterization of serotonin receptor subtypes in the treatment of
Open Access
*Address for Correspondence: Leandro Bueno Bergantin, Department
of Pharmacology – Universidade Federal de São Paulo – Escola Paulista de
Medicina, Laboratory of Autonomic and Cardiovascular Pharmacology - 55
11 5576-4973, Rua Pedro de Toledo, 669 – Vila Clementino, São Paulo – SP,
Brazil, CEP: 04039-032. E-Mail: leanbio39@yahoo.com.br
Received: October 16, 2016; Accepted: December 19, 2016; Published:
December 21, 2016
Clin Pharmacol Transl Med, 2016
Page 1 of 4

depression. Clarifying the mode of action and the interplay of
serotonin receptors with pharmacological agents should help elucidate
antidepressant mechanisms and typical side effects to better
understanding. In addition, clinical medicine featured the novel
antidepressants vortioxetine, vilazodone and milnacipran/
levomilnacipran with regard to their serotonin receptor targets such
as the 5-HT1A, 5-HT3 and 5-HT7, which may account for their
specific effects on certain symptoms of depression as well as a
characteristic side-effect profile [6, 7].
The combination of novel ideas added to improvements on the
discoveries may lead to advances in antidepressant research with the
promise of finding compounds that are both effective, and fast-acting,
including in patients who have tried other therapies with limited
success. In conclusion, new insights for more efficient pharmacological
treatments of depression are clearly needed.
Impact of Ca2+/cAMP Interaction in Clinical Pharmacology
and Translational Medicine
Role of Ca2+/cAMP Interaction in Monoaminergic
Neurotransmission: a review
Several experiments initiated decades ago using catecholaminergic
cells originated the concept of stimulus-secretion coupling to
elucidate neurotransmitter release and hormone secretion. This
concept was initially resulted from the study of cat adrenal gland
perfused with acetylcholine executed by Douglas and Rubin in the
1960s (8). The discovery that increase in the cytosolic Ca2+
concentration ([Ca2+]c) was a basic requirement for exocytosis in
adrenal catecholaminergic cells was made by Baker and Knight in
1970´s [9]. In addition, some studies showed that cAMP raises
neurotransmitter release at many synapses in autonomic nervous
system of vertebrate, including sympathetic and parasympathetic
ganglion neurons [10]. Although the cellular and molecular
mechanisms involved in these synergistic actions of cAMP on the
exocytosis of neurotransmitter and hormones remain uncertain, the
evidences suggest that this intracellular messenger can participate in
fine regulation of exocytosis due to its modulatory action on the
intracellular signaling mediated by Ca2+.
In fact, the hypothesis for an interaction between the intracellular
signalling pathways mediated by Ca2+ and cAMP, named Ca2+/
cAMP interaction, has been extensively studied in many cells and
tissues. Generally, this interaction results in synergistic effects on cell
functions [1, 3, 4, 11, 12] and occurs at the level of adenylyl cyclases
(ACs) or phosphodiesterases (PDEs) [Figure 1]. The Ca2+/cAMP
interaction has particularly been extensively studied at the Ca2+
channels [e.g.: ryanodine receptors (RyR)] of the endoplasmic
reticulum (ER) [1, 3, 4, 11, 12]. Phosphorylation of RyR by protein
kinase A (PKA), and also inositol trisphosphate receptor (IP3R) at
submaximal IP3 concentrations, may increase the open probability of
ER Ca2+ stores, amplifying Ca2+-induced Ca2+ release (CICR)
mechanism and cellular responses [1,3,4] [Figure 1]. Recent evidences
suggest that Ca2+/cAMP interaction participates of exocytosis
regulation in peripheral and central neurons and neuroendocrine cells
[1, 3, 4]. Then, dysfunctions of cellular homeostasis of Ca2+ and/or
cAMP in these cells could result in the dysregulation of Ca2+/cAMP
interaction and exocytotic response, or could be a novel therapeutic
target for medicines [Figure 1].
Figure 1: Role of the Ca2+/cAMP interaction in the regulation of neurotransmitter
release from monoaminergic neurons. Cellular homeostasis of Ca2+ and/or cAMP in
these cells could result in the dysregulation of Ca2+/cAMP interaction and exocytotic
response of monoamines, or could be a novel therapeutic target for medicines, according
to our previous studies [1, 3, 4].
Paradoxical Effects of CCBs and their Pleiotropic
Effects in Depression
Since 1975, several clinical studies have been reporting that acute
and chronic administration of L-type Ca2+ channel blockers (CCBs)
in hypertensive patients, such as nifedipine and verapamil, produces
reduction in peripheral vascular resistance and arterial pressure
associated with an increase in plasma noradrenaline levels and heart
rate, typical signals of sympathetic hyperactivity [13]. However, the
cellular and molecular mechanisms involved in this apparent
sympathomimetic effect of the L-type CCBs remained unclear for
decades. In addition, experimental studies using isolated tissues
richly innervated by sympathetic nerves showed that neurogenic
responses were completely inhibited by L-type CCBs in high
concentrations (>1 μmol/L), but paradoxically potentiated in
concentrations below 1 μmol/L [14,15,16]. During almost four
decades, these enigmatic phenomena named by us as “calcium
paradox” remained unclear.
In 2013, we discovered that this paradoxical increase in
sympathetic activity produced by L-type CCBs is due to its
interference on the Ca2+/cAMP interaction [1,3,4]. Then, the
pharmacological manipulation of the Ca2+/cAMP interaction
produced by combination of the L-type CCBs used in the
antihypertensive therapy, and compounds which increasing
cytosolic cAMP concentration ([cAMP]c enhancer compounds)
used in the anti-depressive therapy such as rolipram, could represent a
Clin Pharmacol Transl Med, 2016
Page 2 of 4

Citation: Swerdlow RH, Lyons KE, Khosla SK, Nashatizadeh M, Pahwa R. A Pilot Study of Oxaloacetate 100 mg Capsules in Parkinson ’s
disease Patients. J Parkinsons Dis Alzheimer Dis. 2016;3(2): 4.
*Address for Correspondence:Leandro Bueno Bergantin,
Rua Pedro de Toledo, 669 – Vila Clementino, São Paulo
– SP, Brazil, CEP: 04039-032. Fax: 1-913-588-0681;
E-mail: rleanbio39@yahoo.com.br
excessive sympathetic hyperactivity caused by increment of
neurotransmitter release from sympathetic neurons. In contrast, the
pharmacological manipulation of Ca2+/cAMP interaction could be
a more efficient therapeutic strategy for increasing serotoninergic
and monoaminergic neurotransmission in psychiatric disorders,
including depression [17].
In addition, several studies have been demonstrating pleiotropic
effects of CCBs. CCBs, like nifedipine, genuinely potentiate the effect
of tricyclic and atypical antidepressants [18,19]. However, the
molecular mechanisms involved in these pleiotropic effects remain
under debate. In fact, apart from its classical functions, CCBs are
described to have beneficiary roles on the cognitive profile of the aged
population and individuals with hypertension, diabetes,
Parkinson’s disease, and Alzheimer’s disease [20-23]. Different
mechanisms have been proposed, but the exact mechanisms of
antidepressant effects and cognitive improvement are still uncertain.
Involvement of
Ca2+/Camp
Interaction: Role in
CCBs
Pleiotropic Effects
In contrast to adverse effects produced by combination of L-type
CCBs with [cAMP]c enhancer compounds in the cardiovascular
diseases, the pharmacological implications of the Ca2+/cAMP
interaction produced by this drug combination could be used to
enhance neurotransmission in central nervous system [1,3,4].
Recent studies have showed that chronic treatment with rolipram,
together with typical antidepressants has been successful in the
reduction of depression symptoms due to potentiation of these
antidepressants effects [24,25,26]. Considering our model in which
increment of [cAMP]c stimulates Ca2+ release from ER [Figure.
1], it may be plausible that the therapeutic use of the PDE
inhibitor rolipram [25, 26], in combination with low doses of
verapamil to potentiate neurotransmission [Figure. 1] in the areas
of central nervous system involved in neurological/psychiatric
disorders in which neurotransmission is reduced, including
depression. This new pharmacological strategy for the treatment
of psychiatric disorders could increase the therapeutic efficacy and
reduce the adverse effects of the medicines currently used for
treating depression. Considering that CCBs genuinely exhibit
cognitive-enhancing abilities and reduce the risk of psychiatric
disorders like depression [19]; and that the mechanisms involved
in these pleiotropic effects are largely unknown. Then, whether Ca2
+/cAMP interaction is involved in such effects deserves special
attention.
In addition, considering [Ca2+]c elevation could contribute to both:
negatively to neuroprotective effects and positively to exocytosis, it
may be plausible the therapeutic use of the PDEs inhibitors [25,26]
for antidepressant purposes. Then, pharmacological interference of
the Ca2+/cAMP interaction produced by combination of L-type
CCBs and [cAMP]c enhancer compounds could enhance
antidepressant response and reduce clinical symptoms of psychiatric
disorders. Thus, the association of currently medicines could enhance
antidepressant treatments. For example: the association of typical
antidepressants with CCBs or rolipram could dramatically improve
typical antidepressant medicines, mainly by reducing their adverse
effects and increasing their effectiveness. This new pharmacological
strategy could be alternatively used for treatment of the symptoms of
psychiatric disorders, including depression.
Conclusion
The diagnosis of psychiatric disorders like depression relies
critically on collaborative history of patients. In addition, emerging
therapies may supplement clinical assessment in the next years.
Although pharmacological therapies have been largely unsuccessful
in curing depression, targeting potential risk factors aiming to
decrease incidence of this psychiatric disorder is an important public
health edge. Finally, novel strategies to treat depression, throughout
our recent discovery entitled “calcium paradox” phenomenon due to
interaction of Ca2+/cAMP intracellular signalling pathways, could
greatly contribute to enhance therapeutic strategies for increasing
neurotransmission [27, 28]. Thus, the association of typical
antidepressants with CCBs or rolipram could dramatically improve
antidepressant therapies, mainly by reducing adverse effects and
improving effectiveness of these typical antidepressants [27].
Disclosure Statement
Caricati-Neto and Bergantin thank the continued financial support
from CAPES, CNPq and FAPESP (Bergantin´s Postdoctoral
Fellowship FAPESP #2014/10274-3).
The authors also thank Elsevier - “author use”: Reuse of portions or
extracts from the article in other works - www.elsevier.com/__data/
assets/pdf_file/0007/55654/AuthorUserRights.pdf
References
1. Caricati-Neto A, García AG, and Bergantin LB. Pharmacological implications of the
Ca2+/cAMP signalling interaction: from risk for antihypertensive therapy to
potential beneficial for neurological and psychiatric disorders. Pharmacol Res
Perspect. 2015; 3:e00181. [Crossref]
2. Pytka K, Podkowa K, Rapacz A, Podkowa A, Żmudzka E, Olczyk A, et al. The role
of serotonergic, adrenergic and dopaminergic receptors in antidepressant-like effect.
Pharmacol Rep. 2016; 68:263-274. [Crossref]
3. Bergantin LB, Souza CF, Ferreira RM, Smaili SS, Jurkiewicz NH, Caricati-Neto
A, et al. Novel model for “calcium paradox” in sympathetic transmission of smooth
muscles: role of cyclic AMP pathway. Cell Calcium. 2013; 54:202-212. [Crossref]
4. Bergantin LB, Jurkiewicz A, García AG, and Caricati-Neto A. A Calcium
Paradox in the Context of Neurotransmission. J Pharma Pharmacol. 2015;
3:253-261. [Crossref]
5. Kaster MP, Moretti M, Cunha MP, and Rodrigues AL. Novel approaches
for the management of depressive disorders. Eur J Pharmacol. 2016; 771:236-240.
[Crossref]
6. Barkin RL, Schwer WA, and Barkin SJ. Recognition and management of depression
in primary care: a focus on the elderly. A pharmacotherapeutic overview of the
selectiosn process among the traditional and new antidepressants. Am J Ther. 2000;
7:205-226. [Crossref]
7. Köhler S, Cierpinsky K, Kronenberg G, and Adli M. The serotonergic system in the
neurobiology of depression: Relevance for novel antidepressants. J
Psychopharmacol. 2016; 30:13-22. [Crossref]
8. Douglas WW, Rubin RP. The role of calcium in the secretory response of t he
adrenal medulla to acetylcholine. J Physiol. 1961; 159:40-57. [Crossref]
9. Baker PF, Knight DE. Calcium-dependent exocytosis in bovine adrenal medullary
cells with leaky plasma membranes. Nature. 1978; 276:620-622. [Crossref]
10. Chern YJ, Kim KT, Slakey LL, and Westhead EW. Adenosine receptors activate
adenylate cyclase and enhance secretion from bovine adrenal chromaffin cells in the
presence of forskolin. J Neurochem. 1988; 50:1484-1493. [Crossref]
11. Cooper DM, Mons N, and Karpen J W. A d enylyl cyclases and the interaction
between calcium and cAMP signalling. Nature. 1995; 374:421-424. [Crossref]
12. Yule DI, Betzenhauser MJ, and Joseph SK. Linking structure to function: recent
lessons from inositol 1,4,5-trisphosphate receptor mutagenesis. Cell Calcium. 2010;
47:469-479. [Crossref]
13. Grossman E, Messerli FH. Effect of calcium antagonists on sympathetic activity. Eur
Heart J. 1998; 19 Suppl. F:F27–F31. [Crossref]
14. Kreye VA, Luth JB. Proceedings: verapamil-induced phasic contractions of the
isolated rat vas deferens. Naunyn Schmiedebergs Arch Pharmacol. 1975; 287
Suppl:R43. [Crossref]
15. French AM, Scott NC. A comparison of the effects of nifedipine and verapamil on rat
vas deferens. Br J Pharmacol. 1981; 73:321-323. [Crossref]
Clin Pharmacol Transl Med, 2016
Page 3 of 4

16. Moritoki H, Iwamoto T, Kanaya J, Maeshiba Y, Ishida Y, and Fukuda H.
Verapamil enhances the non-adrenergic twitch response of rat vas deferens. Eur
J Pharmacol. 1987; 140:75-83. [Crossref]
17. Bergantin LB, Caricati-Neto A. Insight from “Calcium Paradox” due
to Ca2+/cAMP Interaction: Novel Pharmacological Strategies for the
Treatment of Depression. Int Arch Clin Pharmacol. 2016; 2: 007. [Crossref]
18. Prakhie IV, Oxenkrug GF. The effect of nifedipine, Ca(2+) antagonist,
on activity of MAO inhibitors, N-acetylserotonin and melatonin in the mouse
tail suspension test. Int J Neuropsychopharmacol. 1998; 1:35-40. [Crossref]
19. De Vry J, Fritze J, and Post RM. The management of coexisting
depression in patients with dementia: potential of calcium channel
antagonists. Clin Neuropharmacol. 1997; 20:22-35. [Crossref]
20. Ogihara T, Nakagawa M, Ishikawa H, Mikami H, Takeda K, Nonaka H, et al.
Effect of manidipine, a novel calcium channel blocker, on quality of life in
hypertensive patients. Blood Press Suppl. 1992; 3:135-139. [Crossref]
21. Veng LM, Mesches MH, and Browning MD. Age-related working memory
impairment is correlated with increases in the L-type calcium channel protein α1D
(Cav1.3) in area CA1 of the hippocampus and both are ameliorated by chronic
nimodipine treatment. Brain Res Mol Brain Res. 2003; 110:193-202. [Crossref]
22. Chan CS, Guzman JN, I lijic E, Mercer JN, Rick C, Tkatch T, et al.
‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease. Nature.
2007; 447:1081-1086. [Crossref]
23. Tsukuda K, Mogi M, Li JM, Iwanami J, Min LJ, Sakata A, et al. Diabetes-
associated cognitive impairment is improved by a calcium channel blocker,
nifedipine. Hypertension. 2008; 51:528-533. [Crossref]
24. Sommer N, Loschmann PA, Northoff GH, Weller M, Steinbrecher A, Steinbach
JP et al. The antidepressant rolipram suppresses cytokine production and
prevents autoimmune encephalomyelitis. Nat Med. 1995; 1:244-248. [Crossref]
25. Li YF, Cheng YF, Huang Y, Conti M, Wilson SP, O'Donnell JM, et al.
Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down
enhance memory and increase hippocampal neurogenesis via increased cAMP
signaling. J Neurosci. 2011; 31:172-183. [Crossref]
26. Xiao L, O'Callaghan JP, and O'Donnell JM. Effects of repeated treatment with
phosphodiesterase-4 inhibitors on cAMP signaling, hippocampal cell proliferation,
and behavior in the forced-swim test. J Pharmacol Exp Ther. 2011; 338:641-647.
[Crossref]
27. Bergantin LB, Caricati-Neto A. Challenges for the pharmacological t reatment of
neurological and psychiatric disorders: Implications of the Ca2+/cAMP intracellular
signalling interaction. Eur J Pharmacol. 2016; 788:255-260. [Crossref]
28. Bergantin LB, Caricati-Neto A. Novel Insights for Therapy of Parkinson’s
disease: Pharmacological Modulation of the Ca2+/cAMP Signalling Interaction.
Austin Neurol & Neurosci. 2016; 1:1009. [Crossref]
Clin Pharmacol Transl Med, 2016
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