A Calcium Paradox in the Context of Neurotransmission

Abstract

Abstract:The hypothesis of the calcium paradox has its origin in experiments done in neurogenically stimulated rat and mouse vas deferentia. Some old studies reported that reduction of Ca 2+ entry by mild concentrations of verapamil, diltiazem or nifedipine elicited the surprising augmentation of vas deferens contractions. Recent reports have also found that nifedipine caused a paradoxical augmentation of the exocytotic release of catecholamine elicited by paired depolarising pulses in voltage-clamped bovine chromaffin cells. Because these drugs are blocking the L-subtype of VACCs (voltage-activated calcium channels), augmented contraction and exocytosis was an unexpected outcome. Recent experiments in neurogenically-stimulated rat vas deferens have found a more drastic potentiation of contractions with the association of verapamil and cAMP-enhancer compounds. Thus, the interaction between the signalling pathways mediated by Ca 2+ and cAMP could explain those unexpected findings and the so-called calcium paradox.

Emerging Concepts for Neuroscience Field from Ca2+/ cAMP Signalling Interaction

“…In addition, many results have shown that cAMP increases neurotransmitter release at many synapses in autonomic nervous system of vertebrate, including sympathetic neurons [7]. We recently showed that Ca 2+ /cAMP signalling interaction participates in the regulation of transmitters release from sympathetic neurons, and adrenal chromaffin cells [8][9][10][11].…”

“…Thus, elevating [cAMP]c by handling Ca 2+ /cAMP signalling interaction could reduce neuronal death triggered by cytosolic Ca 2+ overload [8][9][10][11]. Then, the pharmacological handling of the Ca 2+ /cAMP signalling interaction produced by combination of the L-type CCBs prescribed in the antihypertensive therapy, and [cAMP] c-enhancer compounds prescribed in the anti-depressive therapy such as rolipram, could be a novel pharmacological strategy for enhancing neurotransmission in neurological, and psychiatric disorders, resulting of neurotransmitter release deficit, and neuronal death [8][9][10][11]. Figure 1 shows how the pharmacological modulation of the Ca 2+ /cAMP signalling by the Nobel laureate Erwin Neher [3].…”

“…This nowadays accepted concept assumes that these signalling pathways virtually exist in all mammalian cells, regulated by adenylyl cyclases (ACs) and phosphodiesterases (PDEs) [8][9][10][11]. Indeed, endoplasmic reticulum (ER) Ca 2+ channels have particularly been a forefront for the Ca 2+ /cAMP signalling interaction field, such as ryanodine receptors (RyR) [8][9][10][11].…”

“…This nowadays accepted concept assumes that these signalling pathways virtually exist in all mammalian cells, regulated by adenylyl cyclases (ACs) and phosphodiesterases (PDEs) [8][9][10][11]. Indeed, endoplasmic reticulum (ER) Ca 2+ channels have particularly been a forefront for the Ca 2+ /cAMP signalling interaction field, such as ryanodine receptors (RyR) [8][9][10][11]. We established that Ca 2+ /cAMP signalling interaction plays a fundamental participation in the regulation of neurotransmitter release from neurons and neuroendocrine cells [8][9][10][11].…”

“…Indeed, endoplasmic reticulum (ER) Ca 2+ channels have particularly been a forefront for the Ca 2+ /cAMP signalling interaction field, such as ryanodine receptors (RyR) [8][9][10][11]. We established that Ca 2+ /cAMP signalling interaction plays a fundamental participation in the regulation of neurotransmitter release from neurons and neuroendocrine cells [8][9][10][11]. Then, Ca 2+ / cAMP signalling interaction could be a novel therapeutic target for medicines.…”