Aspects of astrocytic cAMP signaling with an emphasis on the putative power of compartmentalized signals in health and disease

Abstract

This review discusses aspects of known and putative compartmentalized 3′,5′‐cyclic adenosine monophosphate (cAMP) signaling in astrocytes, a cell type that has turned out to be a key player in brain physiology and pathology. cAMP has attracted less attention than Ca2+ in recent years, but could turn out to rival Ca2+ in its potential to drive cellular functions and responses to intra— and extracellular cues. Further, Ca2+ and cAMP are known to engage in extensive crosstalk and cAMP signals often take place within subcellular compartments revolving around multi‐protein signaling complexes; however, we know surprisingly little about this in astrocytes. Here, we review aspects of astrocytic cAMP signaling, provide arguments for an increased interest in this subject, suggest possible future research directions within the field, and discuss putative drug targets.

Astrocytic Calcium and cAMP in Neurodegenerative Diseases

“…Among the second messengers activated by GPCRs, Ca 2+ , and cyclic adenosine monophosphate (cAMP) are capable of eliciting diverse pleiotropic responses, thus regulating basic cellular functions, such as growth and differentiation, gene transcription and protein expression as well as astrocyte-mediated synaptic plasticity, gliotransmission, energy supply and maintenance of the extracellular environment (Bazargani and Attwell, 2016 ; Horvat and Vardjan, 2019 ; Zhou et al, 2021 ). It is supposed that dysregulation of Ca 2+ and cAMP exacerbates structural and functional abnormalities in this cell type, hence restoration of imbalanced Ca 2+ and/or cAMP signaling may constitute an effective astrocyte-based therapeutic approach Growing body of evidence links deficits in astrocytic Ca 2+ and cAMP-controlled mechanisms to various brain pathologies (Ujita et al, 2017 ; Reuschlein et al, 2019 ; Kofuji and Araque, 2021 ; Zhou et al, 2021 ). Recent technological progress in two-photon imaging and development of genetically encoded Ca 2+ indicators (GECIs) as well as genetically encoded sensors for cAMP and protein kinase A (PKA), allowed for high-resolution detection of astrocytic Ca 2+ /cAMP fluxes in different physiological and pathological conditions (Reeves et al, 2011 ; Gee et al, 2015 ; Semyanov et al, 2020 ; Massengill et al, 2021 ).…”

cAMP Compartmentalization in Cerebrovascular Endothelial Cells: New Therapeutic Opportunities in Alzheimer’s Disease

“…These techniques have allowed for better understanding of the spatial regulation of cAMP and the implication in cellular functionality. Thus, they have made it possible to study cAMP compartmentalization in a wide range of cellular models, including cardiomyocytes [81,82], adipocytes [84], vascular smooth muscle cells [85], neurons [86], or astrocytes [87]. However, despite the great utility of these techniques in studying cell signaling compartmentalization, it should be kept in mind that they are techniques that greatly interfere with normal cell functions, so all results should be viewed with caution, and completed, if possible, with parallel functional studies.…”

Pharmacological inhibition of mitochondrial soluble adenylyl cyclase in astrocytes causes activation of AMP‐activated protein kinase and induces breakdown of glycogen

“…Astrocytes constitute a major cell class among the glial cells found in the brain and the number and morphology of astrocytes are major discriminants of their function among different species (Han et al, 2013; Oberheim et al, 2012; von Bartheld et al, 2016). They are intimately involved in modulation of synaptic plasticity and memory formation and are currently gaining attention in a large variety of brain pathologies as discussed by several authors (Bak et al, 2018; Reuschlein et al, 2019; Skotte et al, 2018; Suzuki et al, 2011; Verkhratsky & Nedergaard, 2018). Interestingly, astrocytes contain the majority of glycogen in the brain and on a cell‐by‐cell basis, they contain more glycogen than muscle cells (Bak et al, 2018; Dienel & Rothman, 2020).…”

“…Interestingly, astrocytes contain the majority of glycogen in the brain and on a cell‐by‐cell basis, they contain more glycogen than muscle cells (Bak et al, 2018; Dienel & Rothman, 2020). The role of glycogen in astrocytes has been widely studied and the metabolism of glycogen, known as glycogenolysis, has been suggested to play an important role in supporting long‐term potentiation (LTP) and memory formation (Reuschlein et al, 2019). Some studies indicate that glycogen supports LTP via shuttling of glycogen‐derived lactate or glutamine from astrocytes to nearby neurons (Reuschlein et al, 2019; Suzuki et al, 2011).…”

“…The role of glycogen in astrocytes has been widely studied and the metabolism of glycogen, known as glycogenolysis, has been suggested to play an important role in supporting long‐term potentiation (LTP) and memory formation (Reuschlein et al, 2019). Some studies indicate that glycogen supports LTP via shuttling of glycogen‐derived lactate or glutamine from astrocytes to nearby neurons (Reuschlein et al, 2019; Suzuki et al, 2011). Inside astrocytes, glycogenolysis can be induced by the second messenger cyclic AMP (cAMP) (Obel et al, 2012); however, it is still not fully understood which signaling pathway(s) may induce glycogenolysis during neuronal activity, although several pathways have been suggested (DiNuzzo et al, 2013).…”