The interaction between intracellular signalling pathways mediated by Ca²⁺ and cAMP (Ca²⁺/cAMP signalling interaction) is now well-accepted as a vital cellular process for mammalians. In the neuroscience field, it has opened a new avenue for the drug development more effective, and safer, for the treatment of Alzheimer´s and neurodegenerative diseases. It has been almost 4 years since we revealed the involvement of the Ca²⁺/cAMP signalling interaction in the enigma of the so-called “calcium paradox”. Interestingly, the “calcium paradox” initiated decades ago, when numerous clinical studies have reported that prescription of L-type Ca²⁺ channel blockers (CCBs) for hypertensive patients decreased arterial pressure, but produced typical symptoms of sympathetic hyperactivity. Despite these adverse effects of CCBs have been initially attributed to adjust reflex of arterial pressure, during almost four decades this enigmatic phenomenon (the socalled “calcium paradox”) remained unclear. In 2013, through creative experiments, we discovered that this phenomenon was resulting of increment of transmitter release from sympathetic neurons, and adrenal chromaffin cells, stimulated by CCBs due to its interference on the Ca²⁺/cAMP signalling interaction. Thus, pharmacological handling of the Ca²⁺/cAMP signalling interaction could be a more efficient and safer therapeutic strategy for stimulating neurotransmission compromised by neurotransmitter release deficit, and attenuating neuronal death.

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