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Abstract

From a "Eureka Insight" to Novel Concepts in Pharmaceutical Sciences: Role of Ca2+/cAMP Intracellular Signalling Interaction

It has been almost 4 years since we revealed the explanation for the enigma of the so-called “calcium paradox”. Our discovery of the involvement of Ca2+/cAMP signaling interaction in the regulation of neurotransmitter release, and neuroprotection, was clearly a serendipitous discovery. It has produced new avenues in the understanding of the cellular and molecular mechanisms involved in the pathogenesis of neurological and psychiatric disorders, such as Alzheimer´s disease. Interestingly, this discovery initiated decades ago when numerous clinical studies have reported that use of L-type Ca2+ channel blockers (CCBs) by hypertensive patients decreased arterial pressure, but produced typical symptoms of sympathetic hyperactivity, such as tachycardia and increment of catecholamine plasma levels. Despite these adverse effects of CCBs have been initially attributed to adjust reflex of arterial pressure, during almost four decades this enigmatic phenomenon (the so-called "calcium paradox") remained unclear. In 2013, through an ingenious experiment, 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 signaling interaction. In this way, our discovery of the role of Ca2+/cAMP intracellular signaling interaction in the neurotransmitter release, and neuronal death triggered by cytosolic Ca2+ overload, opened novel adventures for the development of new pharmacological strategies more effective for the treatment of neurological and psychiatric disorders resulting of neurotransmitter release deficit, and neuronal death. These novel concepts have been extensively documented in several cited international papers of our own authorship (Bergantin and Caricati-Neto), and in an international book.


Author(s):

Leandro Bueno Bergantin and Afonso Caricati-Neto



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