Neonatal and Pediatric Medicine
Open Access

From the past years, it has been shown that the signalling pathways mediated by Ca²⁺ and cAMP can interact (Ca²⁺/cAMP signalling interaction), thus playing a vital role in cellular processes of mammalians. In the neurology and medicine, it could improve therapeutic strategies for stimulating synaptic transmission compromised by transmitter release deficit, and attenuating death of neurons.

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”. For understanding the “calcium paradox”, we should return to the past. Indeed, the concept of stimulus-secretion to elucidate neurotransmitters release has been achieved from creative experiments made by Douglas, et al. [1]. By their concepts, in 1970´s Baker and Knight [2] showed that an increase in the cytosolic Ca²⁺ concentration ([Ca²⁺]c) is a fundamental requirement to start transmitter release. In addition, the unquestionable result showing a correlation between neurotransmitter release and elevation in [Ca²⁺]c came from the interesting experiments made by the Nobel laureate Erwin Neher [3]. Thus, by reducing extracellular Ca²⁺ through blocking Ca²⁺ channels, we should have a reducing in the neurotransmitter release. Nonetheless, many reports have demonstrated that L-type Ca²⁺ channel blockers (CCBs), in concentrations below 1 μmol/L, could induce neurotransmitter release, a “paradox” [4-6]. In addition, many reports have demonstrated that cAMP enhances neurotransmitter release at several synapses in autonomic nervous system of mammalians [7]. Recently, we demonstrated that Ca²⁺/cAMP signalling interaction is implicated in the modulation of transmitters release from sympathetic neurons, and adrenal chromaffin cells [8-11].

The interaction between Ca²⁺ and cAMP signalling pathways as a classical concept: an intriguing history

It is well established that the interaction between Ca²⁺ and cAMP signalling pathways is as a vital cellular process in mammalians [8-11]. This classical concept assumes that these signalling pathways virtually exist in all mammalian cells, modulated by adenylyl cyclases (ACs) and phosphodiesterases (PDEs) [8-11]. In addition, endoplasmic reticulum (ER) Ca²⁺ channels have particularly been a forefront for the interaction between Ca²⁺ and cAMP signalling pathways field, such as Ca²⁺ channels modulated by ryanodine receptors (RyR) [8-11]. We reinforced the idea that the interaction between Ca²⁺ and cAMP signalling pathways plays a fundamental participation in the modulation of neurotransmitter release from neurons and neuroendocrine cells [8-11]. Then, the interaction of Ca²⁺ and cAMP signalling pathways could be a new therapeutic goal for pharmaceuticals.

The interaction between Ca²⁺ and cAMP signalling pathways and neurology

The prescription of L-type CCBs in hypertensive patients has been reported to decrease arterial pressure, but also produces sympathetic hyperactivity [12]. Initially, these adverse effects of CCBs have been attributed to adjust reflex of arterial pressure, but this conclusion remained not completely satisfactory. The year of 2013 would change this history forever! Through a creative experiment, we revealed that the solution for this so-called "calcium paradox" phenomenon was due to the increase of transmitter release from sympathetic neurons achieved by CCBs due to its handling on the interaction between Ca²⁺ and cAMP signalling pathways [9]. We demonstrated that contractions of the smooth muscle (vas deferens) were completely inhibited by Ltype CCBs in high concentrations (>1 μmol/L), but puzzlingly increased in concentrations below 1 μmol/L, thus defined as sympathetic hyperactivity promoted by CCBs [4-6,9]. Our studies clearly established that the contradictory sympathetic hyperactivity is due to an augmentation of transmitter release from sympathetic neurons achieved by L-type CCBs due to its interfering on the interaction between Ca²⁺ and cAMP signalling pathways.

In fact, many reports have shown that elevation of cytosolic cAMP concentration ([cAMP]c) reduces neuronal death resulted from cytosolic Ca²⁺ overload, stimulating neuroprotective effect [13,14]. As mentioned above, the L-type CCBs increase transmitter release due to its handling on the interaction between Ca²⁺ and cAMP signalling pathways. This interference activates ACs, causing elevation of [cAMP]c that, in turn, induces Ca²⁺ release from ER that stimulates transmitter release [8-11]. In addition, this elevation of [cAMP]c produces neuroprotective effects mediated by the Ca²⁺ and cAMP signalling pathways [8-11]. It was proposed that this neuroprotective effect results from activation by cAMP on the cellular survival pathways mediated by PKA/CREB [8-11,13,14]. Then, the pharmacological interfering of the Ca²⁺/cAMP signalling interaction from the combined use of the L-type CCBs prescribed in the antihypertensive therapy, and [cAMP]c-enhancer compounds prescribed in the anti-depressive therapy like rolipram, could be a novel pharmacological goal for increasing neurotransmission in neurological and psychiatric disorders resulted from deficit of neurotransmitter release, and neuronal death [8-11]. 14 illustrates how the pharmacological handling of the interaction between Ca²⁺ and cAMP signalling pathways could produce increase of neurotransmitter release, and attenuation of neuronal death.

Figure 1: Transmitter release stimulation and reduction of neuronal death triggered by Ca²⁺ overload can be achieved due to pharmacological regulation of the interaction between Ca²⁺ and cAMP signalling pathways. In response to the decreasing of Ca²⁺ influx through L-type voltage-activated Ca²⁺ channels produced by CCBs, the adenylyl cyclase activity (and consequently cAMP) is increased. These CCBs-effects can be stimulated by cAMP-enhancer compounds (like PDEs inhibitors). PDEs: Phosphodiesterases, RyR: Ryanodine receptors, IP3R: IP3 receptors, SERCA: Sarcoendoplasmic reticulum Ca²⁺-ATPase.

In fact, it was showed that the prescription of L-type CCBs is able to reduce motor symptoms, and reduces the continued neuronal death in animal model of Parkinson´s disease, indicating that L-type CCBs are potentially workable neuroprotective pharmaceuticals [15]. Intriguingly, a 1-decade study involving thousands senile hypertensive patients demonstrated that prescription of L-type CCBs can reduce blood pressure, and incidence of dementia in hypertensive patients, indicating that these pharmaceuticals could be used to treat neurodegenerative diseases in clinics [16]. These results for the effects related to neuroprotection of CCBs have been reinvestigated in thousands elderly hypertensive patients with dysfunction of memory abilities [17]. These studies concluded that patients who have taken CCBs had their risk of cognitive dysfunction decreased, such as Alzheimer´s disease [17]. These findings reinforce the concept that Ltype CCBs can reduce cytosolic Ca²⁺ overload produced due to blocking of Ca²⁺ influx, and thus could be an alternative pharmacological goal to reduce, or prevent, death of neurons resulted from neurodegenerative diseases.

Based on these findings, we have anticipated that the pharmacological regulation of the Ca²⁺/cAMP signalling interaction by combined use of the L-type CCBs and [cAMP]c-enhancer compounds could be a novel therapeutic goal for increasing neurotransmission in neurological, and psychiatric disorders, resulted from neurotransmitter release deficit and neuronal death [8-11]. This pharmacological strategy opens a novel pathway for the drug development more efficient for the treatment of Alzheimer´s and other neurodegenerative diseases [18-24].

In conclusion, pharmacological interfering of the interaction between Ca²⁺ and cAMP signalling pathways could be a more efficient therapeutic approach for enhancing neurotransmission resulted from neurotransmitter release deficit, and reducing neuronal death. These findings could dramatically impact in neurology and medicine.

Caricati-Neto and Bergantin thank the continued financial support from CAPES, CNPq and FAPESP (Bergantin´s Postdoctoral Fellowship FAPESP #2014/10274-3). The authors also thank Elsevier - “author use”.