Gap junction proteins and their role in spinal cord injury

Abstract

Gap junctions are specialized intercellular communication channels that are formed by two hexameric connexin hemichannels, one provided by each of the two adjacent cells. Gap junctions and hemichannels play an important role in regulating cellular metabolism, signaling, and functions in both normal and pathological conditions. Following spinal cord injury (SCI), there is damage and disturbance to the neuronal elements of the spinal cord including severing of axon tracts and rapid cell death. The initial mechanical disruption is followed by multiple secondary cascades that cause further tissue loss and dysfunction. Recent studies have implicated connexin proteins as playing a critical role in the secondary phase of SCI by propagating death signals through extensive glial networks. In this review, we bring together past and current studies to outline the distribution, changes and roles of various connexins found in neurons and glial cells, before and in response to SCI. We discuss the contribution of pathologically activated connexin proteins, in particular connexin 43, to functional recovery and neuropathic pain, as well as providing an update on potential connexin specific pharmacological agents to treat SCI.

Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology?

“…Of interest, some redundancy and compensation among Cxs appears exists, at least to a limited extent [381]. In addition, Cx and Panx signaling appears to be a double-sided coin as the very same subunits and signaling mechanisms may contribute to the onset as well as the progression of different pathological conditions [14,325]. Hence, it is evident that an accurate fine-tuning of each signaling mechanism is crucial for normal CNS physiology, while a malfunction can lead to pathology.…”

“…Reactive astrogliosis, microglial activation, and neuronal degeneration are common features of many CNS disorders, including stroke, brain trauma, spinal cord injury, epilepsy, and neurodegenerative diseases, such as Alzheimer's Disease [298,299,324,325]. Although clear evidence has been published for a role of neuronal Cx36 GJCs and Panx1 channels in neuronal cell death [104,132,142], many studies also highlight a contribution of the glial cell population [14,99,[325][326][327][328].…”

“…Reactive astrogliosis, microglial activation, and neuronal degeneration are common features of many CNS disorders, including stroke, brain trauma, spinal cord injury, epilepsy, and neurodegenerative diseases, such as Alzheimer's Disease [298,299,324,325]. Although clear evidence has been published for a role of neuronal Cx36 GJCs and Panx1 channels in neuronal cell death [104,132,142], many studies also highlight a contribution of the glial cell population [14,99,[325][326][327][328]. An increasing number of reports demonstrates a profound effect of pathological conditions on the expression of glial Cxs and Panxs, in particular Cx43 and Panx1, and their function as channels in a range of CNS diseases, including epilepsy, traumatic brain and spinal cord injury, Alzheimer's Disease, and ischemia-related injury [14,99,117,[329][330][331][332].…”

Connexin 43: a New Therapeutic Target Against Chronic Kidney Disease

“…The inhibition of Cx43 by ASODNs has been shown to dampen inflammatory responses and promote wound-healing in many tissues including central nervous system [71], skin [72][73][74], skeletal muscle [75], heart [76], smooth muscle [77,78] and vascular endothelium [79][80][81]. Moreover, there are clinical trials using topical application of a gel containing Cx43 AS-ODNs, which have shown a safe and tolerable treatment of skin wounds, venous leg ulcers and diabetic foot ulcers [71]. In our studies, the use of AS-ODNs against Cx43 inhibited renal inflammation and fibrosis and efficiently preserved renal function in animal models of CKD [46,56].…”

Connexin gap junction channels and chronic rhinosinusitis

“…There have also been reports in experimental animal studies and humans of successful therapeutic effects from modulating gap junction channels in order to interrupt the inflammatory cycle, and promote wound healing across a number of different tissues.…”