Calcium/cAMP signaling: Scientific recognition and expertise in the field

Abstract

The calcium (Ca²⁺)/cAMP signaling pathway holds fundamental importance in medicine and physiology; a fact underscored by multiple Nobel Prizes awarded for discoveries in this area, including the initial cAMP recognition in 1971, and subsequent awards related to both cAMP and Ca²⁺. Considering its critical role, continued high-level recognition for research breakthroughs in Ca²⁺/cAMP signaling is anticipated. Reflecting the significance of the pathway, this domain features leading global experts. Notably, Dr. Leandro Bueno Bergantin was designated by Expertscape as a world expert in cAMP (2013-2023), ranking him as the second-highest global authority on the subject based on objective assessments of contributions derived from the PubMed database. Additionally, Dr. Bergantin was recognized as an expert in Ca²⁺ during the same period, highlighting his comprehensive expertise in this vital cellular signaling axis. In this editorial, I comment on the article by Du et al published in the recent issue of the World Journal Psychiatry. The weight of current evidence is now indisputable: the Ca²⁺/ cAMP signaling pathway represents a pivotal molecular intersection in the etiology of psychiatric disorders. It has transcended its historical classification as a mere secondary messenger to emerge as a promising primary pharmacological target.

Key Words: Calcium/cAMP signaling; Psychiatric diseases; Inflammatory diseases; Neurotransmitters

Core Tip: The fundamental importance of the calcium/cAMP signaling pathway in physiology and medicine is highlighted by many Nobel Prizes in the field and the recognition of Dr. Leandro Bueno Bergantin as a world expert in cAMP by Expertscape (2013-2023), confirming his status as a top global authority in this critical cellular axis.

This editorial refers to “Analysis of risk factors for postoperative depressive disorders in patients with intrauterine adhesions” by Du et al, 2026; https://doi.org/10.5498/wjp.v16.i3.112649.

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INTRODUCTION

The landscape of psychiatric research is rapidly shifting away from purely monoaminergic models toward a more complex, systemic view that embraces the role of inflammation and metabolic health[1-3]. Mounting evidence suggests that the comorbidity often observed between inflammatory diseases – such as obesity and metabolic syndrome - and major psychiatric disorders, notably depression, is not coincidental[1,4,5]. It appears to share a deep-rooted molecular mechanism centered on cellular communication. Specifically, the calcium (Ca²⁺)/cAMP signaling pathway[1-5].

The relevance of this pathway is clearly validated by its historical scientific acclaim, demonstrated by the many Nobel Prizes awarded for discoveries related to cAMP (beginning in 1971) and Ca²⁺[6-11]. In this critical field, Dr. Leandro Bueno Bergantin has been recognized by Expertscape as a world expert in cAMP (2013-2023), ranking him as the second-highest global authority on the subject based on objective assessments of contributions derived from the PubMed database, lending significant authority to the concept of Ca²⁺/cAMP dysregulation as a primary link[1-5]. In this editorial, Dr. Bergantin comments on the study by Du et al[12] published in the recent issue of the World Journal Psychiatry, which analyzed the risk factors for depression after intrauterine adhesions surgery. Building on these findings, he further explores the underlying mechanisms, particularly Ca²⁺/cAMP signaling pathways as key causal mediators.

THE NUTRITIONAL NEXUS AND cAMP DOWNREGULATION

A recent and highly pertinent report published in 2025[13] provides compelling new validation for this signaling connection[1-5]. This study[13] elegantly demonstrated that a diet lacking essential nutrients worsened neuropsychiatric symptoms in APP/PS1 mice, validating the concept of interplay between inflammation and nutrition[13]. Crucially, the authors found that malnutrition was directly associated with downregulation of the cAMP signaling pathway within key affective brain regions; specifically, the midbrain and striatum[13]. This finding reinforces previous work, including our own[1-4], which hypothesized that dysregulation of the Ca²⁺/cAMP pathway might serve as the initial mechanism connecting conditions like obesity and depression, impacting neurotransmitter and hormone release[1-4]. A decrease in cAMP/PKA signaling impairs synaptic plasticity and contributes to depression[1,4], whereas pathway stimulation is linked to rapid antidepressant effects[4,13].

VALIDATING THE UNIFIED THEORY

This body of work[1-5,13,14] significantly contributes to the validation of our unified theory[3] connecting inflammation and Ca²⁺/cAMP signaling. This conceptual framework has been further supported by longitudinal clinical data[14]. A cross-sectional and longitudinal analysis by Chou et al[14] (2010-2016, baseline n = 27364 patients) concluded that higher serum Ca²⁺ levels were associated with an enhanced risk of inflammatory disorders, including metabolic syndrome, diabetes, and hypertension. Thus, the systemic impact of Ca²⁺ dysregulation is undeniable, corroborating our mechanistic findings (Figure 1)[1-5]. In addition, blockade of Ca²⁺ channels has been observed to elevate cognitive performance, confer protection against parkinsonian symptoms, and mitigate diabetic symptomatology[1,2,15]. These actions are potentially mediated by the reduction of excessive Ca²⁺ accumulation within the cytosol and the modulation of the interconnected Ca²⁺ and cAMP cellular signaling cascade (Figure 1)[1,2,15].

Figure 1 Chronic increasing calcium levels through an inflammatory stimulus reduces cAMP levels, leading to inflammatory diseases. AC: Adenylyl cyclase; PDE: Phosphodiesterase; Up arrow: Increasing; Down arrow: Decreasing.

POSTOPERATIVE DEPRESSION AND PSYCHOLOGICAL VULNERABILITY

The rate of postoperative depression identified in the study by Du et al[12] is notably high when contrasted with the general female population, where typical depression rates span from 5% to 12%[16-18]. Nevertheless, this prevalence is comparable to the rates reported in women suffering from other gynecological inflammatory conditions that compromise fertility and reproductive function. For instance, studies on endometriosis patients indicate depression rates of 24% to 38%[19], while infertility patients show rates of 15%-30%[20]. These findings imply that reproductive health issues may establish a specific psychological vulnerability for women, particularly when there is a potential effect on fertility and family planning[21].

The pathophysiology of postoperative depression is complex and likely involves several mechanisms[22]. Fluctuations in reproductive hormones, especially estrogen, have well-established influences on the neurotransmitter systems responsible for mood regulation[23]. Inflammatory processes implicated in both postoperative condition and depression may represent another connection, as proinflammatory cytokines are associated with the development of depression[3,4]. The same concept could be extrapolated for the link between endometriosis and depression, considering endometriosis is an inflammatory disease. Our research, supported by several studies[1-5], indicates a robust connection between the impaired regulation of Ca²⁺ signaling and the development of inflammation (Figure 1). Our collective body of work[1-5] has demonstrated that elevated concentrations of cAMP can trigger the release of Ca²⁺ from the endoplasmic reticulum, underscoring the vital interaction between the Ca²⁺ and cAMP signaling pathways. Intriguingly, this system includes a negative feedback loop: Increased Ca²⁺ levels can subsequently lead to a reduction in cAMP concentrations (Figure 1). Any disturbance in this crucial Ca²⁺/cAMP signaling balance may be a contributing factor in both postoperative condition and depression[1-5].

CONCLUSION

The cAMP signaling pathway serves as a pivotal, highly localized regulator connecting neuroinflammation with psycho-neuroendocrinology, holding deep relevance for psychiatric conditions[2,3,24,25]. Initial research confirmed the importance of cAMP downstream of G protein-coupled receptors, where it activates protein kinase A to facilitate essential synaptic functions and cognition[25]. More recent findings emphasize that cAMP activity, tightly controlled by phosphodiesterases (PDEs) and exchange proteins activated by cAMP, actively orchestrates anti-inflammatory processes and contributes to the resolution phase of inflammation[26,27]. PDEs are key hydrolytic enzymes that terminate cAMP signaling, and their various isoforms (e.g., PDE4) are strategically localized within cellular compartments, effectively creating distinct signaling domains. Specific PDE isoforms are upregulated in reactive glial cells and immune cells under neuroinflammatory conditions, leading to localized suppression of anti-inflammatory cAMP levels[28]. This compartmentalized dysregulation has made PDE inhibitors a major focus for developing novel therapeutic strategies aimed at restoring the anti-inflammatory and proresolving effects of cAMP within the central nervous system[28]. Psycho-neuroendocrinology investigations reveal that chronic psychological stress and associated hormonal shifts, notably surges in glucocorticoids and catecholamines, critically impact brain cytokine production and neuroinflammation[29], implying a mechanism by which stress hormones may modulate cAMP-regulated function in neuronal and glial cells, potentially contributing to the development of disorders such as post-traumatic stress disorder and major depressive disorder[30,31]. This intricate understanding strongly supports the development of targeted treatments for neuroinflammatory and stress-related illnesses via modulation of the cAMP cascade.

The evidence is now too compelling to ignore. The Ca²⁺/cAMP signaling pathway is emerging as a crucial molecular nexus in psychiatric pathophysiology, moving beyond its traditional role as a secondary messenger to become a potential primary therapeutic target[1,2]. I urge the psychiatric research community to shift focus toward understanding how Ca²⁺/cAMP-modulating agents could be developed for fast-acting interventions[3,4]. These findings emphasize the necessity of integrating nutritional status and inflammatory markers (such as serum Ca²⁺) into routine clinical assessment, recognizing that a systemic dysregulation may be driving the affective symptoms we treat[5]. By viewing the brain not in isolation, but as an integral part of an inflamed, metabolically challenged system, we can unlock novel and more effective treatments for our patients[5].