Pharmaceutical intervention on Ca 2 + / cAMP signaling interaction : benefits for combating neurodegeneration and diseases related to aging

The pharmaceutical intervention on the interaction between intracellular signaling pathways mediated by Ca and cAMP (Ca/cAMP signaling interaction) could bring important benefits for combating neurodegeneration and diseases related to aging. This discovery emerged from classical neurotransmission studies using rodent vas deferens as a model. From classical reports using this model, the concept of Ca-dependent processes involved in the neurotransmission (Ca influx triggers muscle contraction and neurotransmitter release) is amply accepted. Thus, Ca channel blockers (CCB) due to reduction of Ca influx through L-type voltageactivated Ca channels (VACC) should reduce neurotransmission. Nonetheless, using this model, some studies performed since 1975 reported that reduction of Ca influx by low concentrations of CCB (verapamil, diltiazem or nifedipine) produced a paradoxical increase of the contractions mediated by sympathetic nerves, a phenomenon known as “calcium paradox”. Recent studies using adrenal chromaffin cells have also demonstrated that CCB caused a paradoxical increase of the catecholamine release. Because these compounds are blocking the L-type VACC, an augmented nerve-mediated response due to increased neurotransmitter release was an unexpected outcome. In 2013, we revealed that the Ca/cAMP signaling interaction could properly explain the so-called “calcium paradox”. The original paper published by us in Cell Calcium (2013) has appeared four times in ScienceDirect TOP 25 Hottest Articles lists. In conclusion, these findings may significantly impact on neurodegenerative diseases, thus may stimulate the development of new pharmacological strategies to combat the diseases related to aging. Corresponding author: Leandro Bueno Bergantin Department of Pharmacology – Universidade Federal de São Paulo – Escola Paulista de Medicina, Laboratory of Autonomic and Cardiovascular Pharmacology – Tel.: 55 11 5576-4973, Rua Pedro de Toledo, 669 – Vila Clementino, São Paulo – SP, Brazil, CEP: 04039-032. Email: leanbio39@yahoo.com.br


Introduction
From basic science, we know that in mammals, neurotransmission in the vas deferens [10,11].In an old report, however, it was showed that verapamil inhibited the sympathetic contractions of the rat smooth muscles (vas deferens), as predictable; nevertheless, this report also described that the low concentrations of verapamil produced a surprising increase of those neurogenic contractions [6].This paradoxical effect was corroborated in 1981 by French and Scott [12], also in these contractions.Furthermore, six years later a third study reported that verapamil and diltiazem increased these sympathetic contractions; this result was attributed to an agonist effect of CCB on L-type VACC, thus increasing Ca2+ influx and neurotransmitter release [13].Another published report (two years later) revealed that both, L-type VACC blockers and activator BAY K 8644, elicited similar increases of the neurogenic contractions of the smooth muscles (vas deferens) mediated by sympathetic nerves; the authors did not provide a reasonable explanation for such paradoxical observation [14].
In as observed in the presence of CCB and cAMP enhancers [8].Thus, these findings can dramatically impact on the cardiovascular, neurodegenerative disorders, cancer and other diseases related to aging [15][16][17].
Based on these findings, we have anticipated that the pharmacological modulation of the Ca2+/cAMP signaling interaction by combined use of the L-type CCB and cAMP-enhancer compounds could be a novel therapeutic goal for increasing neurotransmission in neurological, and psychiatric disorders, resulted from neurotransmitter release deficit, and neuronal death [15,16].This neuroprotector strategy opens a novel pathway for the drug development which is more In conclusion, the Ca2+/cAMP signaling interaction may dramatically impact on medical research and therapeutics, stimulating the development of new pharmacological strategies for the therapy of human diseases, including: neurodegenerative diseases, and yet cellular therapy using stem cells for combating diseases related to aging.

Aging
increases of the concentration of free Ca2+ ions in the cytosol ([Ca2+]c) serve as a messenger signal to couple 2].A huge number of experiments performed since the discovery of the role of Ca2+ in the control of the heart beat [3] have set the dogma that in excitable cells, the increased Ca2+ influx by voltageactivated Ca2+ channels (VACC) elicited by depolarising stimuli, triggers muscle contraction and the release of neurotransmitters, and hormones.Conversely, the mitigation of Ca2+ influx produced by VACC blockers causes a reduction of those responses [4,5].The above concepts imply that the enhanced Ca2+ entry during cell depolarisation and/or enhanced Ca2+ release from the sarco-endoplasmic reticulum (ER) augments the [Ca2+]c and the triggering of the contractile, or secretory responses.However, about four decades ago, a study showed that verapamil at low concentrations produced a paradoxical increase of the contractions mediated by sympathetic nerves from vas deferens [6].On the other hand, nifedipine was recently found to paradoxically augment the exocytosis of catecholamine triggered by double-pulse depolarisations from voltageclamped bovine adrenal chromaffin cells, another interesting model to study sympathetic neurotransmission [7].How these two L-type VACC blockers can enhance, instead of reducing, the Ca2+dependent contractile and secretory responses?We properly gave a response to this "calcium paradox" in 2013 through the Ca2+/cAMP signaling interaction [8].In the vas deferens, both release and postsynaptic actions of noradrenaline (NA), and other neurotransmitters such as adenosine 5´ triphosphate (ATP), depend on Ca2+ influx by VACC, and the ensuing elevations of [Ca2+]c [9].Hence, some authors found that verapamil abolished both noradrenergic and purinergic components of the sympathetic

efficient and safe for the therapy ofFigure 1 .
Figure 1.Pharmacological modulation of the Ca 2+ /cAMP signaling interaction proposed by Caricati-Neto and Bergantin [15,16].The Ca 2+ /cAMP signaling interaction can be pharmacologically modulated by combined use of drugs that reduce [Ca 2+ ]c such as CCB, and cAMP-enhancer compounds such as PDE inhibitors and AC activators.This pharmacological modulation could be a new strategy to attenuate neuronal death caused by cytosolic Ca 2+ overload and to increase neurotransmitter release.L, N, PQ: Ca 2+ channel types; PDE: phosphodiesterase; RyR: ryanodine receptors; IP 3 R: IP 3 receptors; SERCA: sarcoendoplasmic reticulum Ca 2+ -ATPase; (+): stimulation; dotted arrow: weak effect; solid arrow: strong effect.