Connexins and pannexins: At the junction of neuro‐glial homeostasis &amp; disease

Lapato, Andrew; Tiwari‐Woodruff, Seema K.

doi:10.1002/jnr.24088

Cited by 69 publications

(65 citation statements)

References 136 publications

(330 reference statements)

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“…Cytokine signaling is now known to exert direct effects upon neural signaling through eponymous receptors located on neurons, microglia, and astrocytes, in the spinal parenchyma and in the DRG and brain. Further, while neuronal activation might be the result of receptor-mediated and direct cell-to-cell contact-dependent mechanisms (e.g., gap junction contacts in DRG neurons and satellite cells) (5), soluble extracellular molecules serve to create broader gradients of paracrine-and autocrine-like regulatory networks. These cytokines thus comprise a communication network between immune and neuronal cells.…”

Section: Introductionmentioning

confidence: 99%

Neuraxial Cytokines in Pain States

et al. 2020

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A high-intensity potentially tissue-injuring stimulus generates a homotopic response to escape the stimulus and is associated with an affective phenotype considered to represent pain. In the face of tissue or nerve injury, the afferent encoding systems display robust changes in the input-output function, leading to an ongoing sensation reported as painful and sensitization of the nociceptors such that an enhanced pain state is reported for a given somatic or visceral stimulus. Our understanding of the mechanisms underlying this non-linear processing of nociceptive stimuli has led to our appreciation of the role played by the functional interactions of neural and immune signaling systems in pain phenotypes. In pathological states, neural systems interact with the immune system through the actions of a variety of soluble mediators, including cytokines. Cytokines are recognized as important mediators of inflammatory and neuropathic pain, supporting system sensitization and the development of a persistent pathologic pain. Cytokines can induce a facilitation of nociceptive processing at all levels of the neuraxis including supraspinal centers where nociceptive input evokes an affective component of the pain state. We review here several key proinflammatory and anti-inflammatory cytokines/chemokines and explore their underlying actions at four levels of neuronal organization: (1) peripheral nociceptor termini; (2) dorsal root ganglia; (3) spinal cord; and (4) supraspinal areas. Thus, current thinking suggests that cytokines by this action throughout the neuraxis play key roles in the induction of pain and the maintenance of the facilitated states of pain behavior generated by tissue injury/inflammation and nerve injury.

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Section: Introductionmentioning

confidence: 99%

Neuraxial Cytokines in Pain States

et al. 2020

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“…Additionally, Cx26, Cx30, Cx40, Cx45, and Cx46 mRNA has been detected in cultured astrocytes from Cx43 KO mice (Dermietzel, 2000), mRNA for Cx26, Cx30, Cx32, Cx40, and Cx43 has also been detected by single-cell RT-PCR in hippocampal astrocytes (Blomstrand, 2004), and GJs in cultured astrocytes are mainly composed of Cx43 (Dermietzel, 1991;Giaume, 1991). Cxs in astrocytes, oligodendrocytes, microglia and neurons are characterized according to the developmental state, region and cell-type specific isoform expression, suggesting that Cxs play a critical role in the regulation and maintenance of various CNS functions (Lapato and Tiwari-Woodruff, 2018). Cx43 is ubiquitously expressed in astrocytes throughout the brain, and along with Cx26 and Cx30, contributes to the interconnection of the astrocyte network (Rash, 2001); however, Cx26 and Cx30 are less abundant in astrocytes (Contreras, 2004).…”

Section: Astrocytes and Connexins During Inflammationmentioning

confidence: 99%

“…Cx43 is ubiquitously expressed in astrocytes throughout the brain, and along with Cx26 and Cx30, contributes to the interconnection of the astrocyte network (Rash, 2001); however, Cx26 and Cx30 are less abundant in astrocytes (Contreras, 2004). This expression profile probably determines the autocrine and paracrine signaling interaction that mediates glial and neuroglial communication (Lapato and Tiwari-Woodruff, 2018). Importantly, Cx43 is upregulated under inflammatory conditions and in astrocytes derived from transgenic hSOD G93A mice, which is an animal model of ALS.…”

Section: Astrocytes and Connexins During Inflammationmentioning

confidence: 99%

Connexins in Astrocyte Migration

et al. 2020

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Astrocytes have long been considered the supportive cells of the central nervous system, but during the last decades, they have gained much more attention because of their active participation in the modulation of neuronal function. For example, after brain damage, astrocytes become reactive and undergo characteristic morphological and molecular changes, such as hypertrophy and increase in the expression of glial fibrillary acidic protein (GFAP), in a process known as astrogliosis. After severe damage, astrocytes migrate to the lesion site and proliferate, which leads to the formation of a glial scar. At this scarforming stage, astrocytes secrete many factors, such as extracellular matrix proteins, cytokines, growth factors and chondroitin sulfate proteoglycans, stop migrating, and the process is irreversible. Although reactive gliosis is a normal physiological response that can protect brain cells from further damage, it also has detrimental effects on neuronal survival, by creating a hostile and non-permissive environment for axonal repair. The transformation of astrocytes from reactive to scar-forming astrocytes highlights migration as a relevant regulator of glial scar formation, and further emphasizes the importance of efficient communication between astrocytes in order to orchestrate cell migration. The coordination between astrocytes occurs mainly through Connexin (Cx) channels, in the form of direct cell-cell contact (gap junctions, GJs) or contact between the extracellular matrix and the astrocytes (hemichannels, HCs). Reactive astrocytes increase the expression levels of several proteins involved in astrocyte migration, such as a v b 3 Integrin, Syndecan-4 proteoglycan, the purinergic receptor P2X7, Pannexin1, and Cx43 HCs. Evidence has indicated that Cx43 HCs play a role in regulating astrocyte migration through the release of small molecules to the extracellular space, which then activate receptors in the same or adjacent cells to continue the signaling cascades required for astrocyte migration. In this review, we describe the communication of astrocytes through Cxs, the role of Cxs in inflammation and astrocyte migration, and discuss the molecular mechanisms that regulate Cx43 HCs, which may provide a therapeutic window of opportunity to control astrogliosis and the progression of neurodegenerative diseases.

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“…Connexins are a family of trans-membrane proteins related to several functions, such as, intercellular communication and tissue differentiation. These proteins are best known for being the assembling subunits of connexons, a hexameric structure composed of six units of connexins [72][73][74]. The apposition of connexons in adjacent cells forms intercellular conduits named gap junctions (GJs), which allow the transfer of small molecules, ions and second messengers between cells [75].…”

Section: Connexinsmentioning

confidence: 99%

The Role of Purinergic Signaling in the Pathophysiology of Perinatal Hypoxic-Ischemic Encephalopathy

Morais-Lima¹,

Vicentini²,

Alberto³

et al. 2020

Receptors P1 and P2 as Targets for Drug Therapy in Humans

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Perinatal hypoxic-ischemic encephalopathy (HIE), known as birth asphyxia, remains a major contributor to poor neurodevelopmental outcomes including cerebral palsy and seizures. One striking feature of HIE injury is a delayed progression of neuronal degeneration that spreads over time from the most severely damaged areas outward into neighboring undamaged regions. There is increasing evidence that these lesions act as sites of origin for waves of spreading depression (SD), a wave of neuronal and glial depolarization, that progressively enlarge the brain lesions. While the pathophysiology of SD is still under debate, there is increasing evidence that purinergic receptors in conjunction with connexin and pannexin 1 channels are necessary for sustained propagation of the waves and neuroinflammation. This review intends to discuss the relative contribution of purinergic signaling and connexin and pannexin 1 channels to trigger and spread SD waves leading to the development of progressive brain lesions under conditions of perinatal HIE.

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Connexins and pannexins: At the junction of neuro‐glial homeostasis & disease

Cited by 69 publications

References 136 publications

Neuraxial Cytokines in Pain States

Neuraxial Cytokines in Pain States

Connexins in Astrocyte Migration

The Role of Purinergic Signaling in the Pathophysiology of Perinatal Hypoxic-Ischemic Encephalopathy

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