In the cardiovascular field, tachycardia and increment of catecholamine plasma levels (sympathetic hyperactivity) have been reported by hypertensive patients that use L-type Ca²⁺ channel blockers (CCBs) since 70´s. Our discovery of the involvement of interaction between the intracellular signalling pathways mediated by Ca²⁺ and cAMP (Ca²⁺/cAMP interaction) revealed that this phenomenon (sympathetic hyperactivity) was resulting of increase of transmitter release from sympathetic neurons stimulated by CCBs due to its interference on the Ca²⁺/cAMP interaction. In the neuroscience field, this discovery has produced new paths for the understanding of the cellular and molecular mechanisms involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer´s and Parkinson’s diseases. In this way, novel journeys for the development of new pharmacological strategies more effective for the treatment of neurodegenerative diseases may be initiated.

Many results have shown that cAMP increases neurotransmitter release at many synapses in autonomic nervous system of vertebrate, including sympathetic neurons [1]. The notion of stimulus-secretion initially resulted from the experiments performed by Douglas and Rubin in the 1960s [2]. Using adrenal chromaffin cells, Baker and Knight revealed in 1970´s that a rise in the cytosolic Ca²⁺ concentration ([Ca²⁺] c) is an elementary requirement to trigger transmitter release [3]. The demonstration of direct relationship between rapid neurotransmitter release and rise in [Ca²⁺]c derived from the experiments using photo released caged Ca²⁺ in adrenal chromafin cells performed Neher and Zucker in 1990´s [4]. Although the cellular and molecular mechanisms involved in these synergistic effects of cAMP on the release of neurotransmitter and hormones are indistinct, the evidences suggest that this important intracellular messenger modulates intracellular signalling mediated by Ca²⁺ involved in the regulation of neurotransmitter, and hormones release.

The ca²⁺/camp interaction hypothesis

The hypothesis for a suitable interaction between the intracellular signalling pathways mediated by Ca²⁺ and cAMP, named Ca²⁺/cAMP interaction, has been widely studied in different cell types and tissues. The Ca²⁺/cAMP interaction has particularly been extensively studied at the endoplasmic reticulum (ER) Ca²⁺ channels, such as Ca²⁺ channels regulated by ryanodine receptors (RyR) [5-8]. In general, this interaction results in synergistic actions of these intracellular messengers on cell functions regulated by adenylyl cyclases (ACs), or phosphodiesterases (PDEs) [5-8]. Indeed, Ca²⁺/cAMP interaction plays a role in neurotransmitter release from neurons and neuroendocrine cells [5-8]. Then, novel therapeutic insights for medicines could be developed by the pharmacological modulation of the Ca²⁺/cAMP interaction.

The ca²⁺/camp interaction: new insights for neuroscience

Sympathetic hyperactivity such as tachycardia, and increment of catecholamine plasma levels, have been evidenced by several medical studies dealing with CCBs [9]. Despite these adverse effects of CCBs have been initially attributed to adjust reflex of arterial pressure, during almost four decades the cellular and molecular mechanisms involved this enigmatic phenomenon named “calcium paradox” remained unclear.

In 2013, we revealed that “calcium paradox” phenomenon resulted from the increment of transmitter release from sympathetic neurons, and adrenal chromaffin cells, stimulated by CCBs due to its interference on the Ca²⁺/cAMP interaction [6]. Using isolated tissues richly innervated by sympathetic nerves (rat vas deferens) to exclude the influence of adjusting reflex, we showed that neurogenic responses 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 sympathetic hyperactivity induced by CCBs [10-12]. Indeed, this paradoxical sympathetic hyperactivity is caused by increment of neurotransmitter release from sympathetic neurons due to its pharmacological modulation on the Ca²⁺/cAMP interaction [5-8] (Figure 1).

Undeniably, several studies showed that neuroprotective response can be achieved by increase of cytosolic cAMP concentration ([cAMP] c) stimulation [13,14]. In this way, we could propose that a rise of [cAMP]c by interfering in the Ca²⁺/cAMP interaction could attenuate neuronal death triggered by cytosolic Ca²⁺ overload [5-8,15,16]. Then, the pharmacological modulation of the Ca²⁺/cAMP interaction [17,18] produced by combination of the L-type CCBs used in the antihypertensive therapy, and [cAMP]c enhancer compounds used in the anti-depressive therapy such as rolipram, could be a new pharmacological strategy for enhancing neurotransmission in neurological and psychiatric disorders [19,20] resulting from neurotransmitter release deficit, and/or neuronal death [5-8,15,16]. These results could open a new path for the drug development more effective and safer for the treatment of neurodegenerative diseases.

New insights for the neuroscience field from the discovery of the “calcium paradox” due to Ca²⁺/cAMP interaction have been emerging to treat neurodegenerative diseases. Pharmacological modulation of this interaction could be a more efficient and safer therapeutic strategy for stimulating neurotransmission compromised by neurotransmitter release deficit, and attenuating neuronal death in the neurodegenerative diseases.

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- https://www.elsevier.com/__data/assets/pdf_file/0007/55654/AuthorUserRights.pdf

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