The “Calcium Paradox” Due To Ca2+/Camp Interaction: New Insights for the Neuroscience Field

In the cardiovascular fi eld, 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 fi eld, 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. Short Communication


INTRODUCTION
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 chromaf in cells, Baker and Knight revealed in 1970´s that a rise in the cytosolic Ca 2+ concentration ([Ca 2+ ] c) is an elementary requirement to trigger transmitter release [3]. The demonstration of direct relationship between rapid neurotransmitter release and rise in [Ca 2+ ] c derived from the experiments using photo released caged Ca 2+ in adrenal chroma in 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 Ca 2+ 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 Ca 2+ and cAMP, named Ca 2+ /cAMP interaction, has been widely studied in different cell types and tissues. The Ca 2+ /cAMP interaction has particularly been extensively studied at the endoplasmic reticulum (ER) Ca 2+ channels, such as Ca 2+ channels regulated by ryanodine receptors (RyR) [5][6][7][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][6][7][8]. Indeed, Ca 2+ /cAMP interaction plays a role in neurotransmitter release from neurons and neuroendocrine cells [5][6][7][8]. Then, novel therapeutic insights for medicines could be developed by the pharmacological modulation of the Ca 2+ /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 re lex 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 chromaf in cells, stimulated by CCBs due to its interference on the Ca 2+ /cAMP interaction [6]. Using isolated tissues richly innervated by sympathetic nerves (rat vas deferens) to exclude the in luence of adjusting re lex, 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][11][12]. Indeed, this paradoxical sympathetic hyperactivity is caused by increment of neurotransmitter release from sympathetic neurons due to its pharmacological modulation on the Ca 2+ / cAMP interaction [5][6][7][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 Ca 2+ /cAMP interaction could attenuate neuronal death triggered by cytosolic Ca 2+ overload [5][6][7][8]15,16]. Then, the pharmacological modulation of the Ca 2+ /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 de icit, and/or neuronal death [5][6][7][8]15,16]. These results could open a new path for the drug development more effective and safer for the treatment of neurodegenerative diseases. Figure 1: Increase of the neurotransmitter release due to pharmacological modulation of the Ca 2+ /cAMP interaction by L-type CCBs [5][6][7][8].