Pharmaceutical Intervention On Ca2+/camp Signaling Interaction: Benefits For Combating Neurodegeneration and Diseases Related To Aging - Pharmaceutical Intervention On Ca2+/camp Signaling Interaction: Benefits For Combating Neurodegeneration and Diseases Related To Aging - Open Access Pub

DOI10.14302/issn.2577-2279.ijha-17-1587 The pharmaceutical intervention on the interaction between intracellular signaling pathways mediated by Ca2+ and cAMP (Ca2+/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 Ca2+-dependent processes involved in the neurotransmission (Ca2+ influx triggers muscle contraction and neurotransmitter release) is amply accepted. Thus, Ca2+ channel blockers (CCB) due to reduction of Ca2+ influx through L-type voltage-activated Ca2+ channels (VACC) should reduce neurotransmission. Nonetheless, using this model, some studies performed since 1975 reported that reduction of Ca2+ 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 Ca2+/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. From basic science, we know that in mammals, increases of the concentration of free Ca2+ ions in the cytosol ([Ca2+]c) serve as a messenger signal to couple the stimulus to muscle contraction, or to neurotransmitter release, among other physiological responses 1, 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 voltage-activated 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