Connexin 43 and ATP-sensitive potassium channels crosstalk: a missing link in hypoxia/ischemia stress

Abstract

Connexin 43 (Cx43) is a gap junction protein expressed in various tissues and organs of vertebrates. Besides functioning as a gap junction, Cx43 also regulates diverse cellular processes like cell growth and differentiation, cell migration, cell survival, etc. Cx43 is critical for normal cardiac functioning and is therefore abundantly expressed in cardiomyocytes. On the other hand, ATP-sensitive potassium (K) channels are metabolic sensors converting metabolic changes into electrical activity. These channels are important in maintaining the neurotransmitter release, smooth muscle relaxation, cardiac action potential repolarization, normal physiology of cellular repolarization, insulin secretion and immune function. Cx43 and K channels are part of the same signaling pathway, regulating cell survival during stress conditions and ischemia/hypoxia preconditioning. However, the underlying molecular mechanism for their combined role in ischemia/hypoxia preconditioning is largely unknown. The current review focuses on understanding the molecular mechanism responsible for the coordinated role of Cx43 and K channel protein in protecting cardiomyocytes against ischemia/hypoxia stress.

Diazoxide Needs Mitochondrial Connexin43 to Exert Its Cytoprotective Effect in a Cellular Model of CoCl2-Induced Hypoxia

“…It has been demonstrated that ischemic preconditioning causes a very rapid increase in mCx43 levels [ 7 , 26 ], and early studies report that mCx43 plays an essential role in preventing apoptotic cell death [ 5 ]. Additionally, the opening of K ATP channels has been reported as a part of the complex cytoprotective program activated during hypoxia [ 2 , 26 ].…”

“…However, cells respond to hypoxia by complex metabolic reprogramming and molecular mechanisms aimed to minimize the detrimental consequences of oxygen deprivation on mitochondria [ 2 ]. Cytoprotective programs activated during hypoxia injury integrate several processes, including the hypoxia-inducible factor 1/hypoxia response element pathway [ 3 ], translocation of connexin43 (Cx43) to the inner mitochondrial membrane [ 4 ] and opening of the mitochondrial ATP-regulated potassium (mitoK ATP ) channels [ 5 ].…”

The Effect of Intra Spinal Administration of Cerium Oxide Nanoparticles on Central pain mechanism: An Experimental Study Running Title: CeONP Administration Effect on Chronic Pain

“…Additionally, GJs perform crucial functions in controlling cellular metabolism, signaling, and other processes. Under typical circumstances, neurons are encompassed by astrocytes and other glial cells that are coupled by an optimal number of GJ channels (53). However, pathological conditions, such as neural injuries, activated astrocytes, and increased Cx43 expression can lead to a surge in GJ formation and the release of ATP into the extracellular space.…”

“…The neuron's purinergic receptors can be activated through the elevation of extracellular ATP levels, which leads to central sensitization and NP induction (54). Studies have shown that NP can be signi cantly diminished via Cx43 inhibitors, providing a potential treatment approach for NP (53). Furthermore, alterations in the expression of Cx43 in in ammatory regions may impact alterations in astrocytic phenotype (55).…”

Connexin Gap Junctions and Hemichannels in Modulating Lens Redox Homeostasis and Oxidative Stress in Cataractogenesis

“…In cardiomyocytes, the translocation of Cx43 to the mitochondrial inner membrane exerts cardioprotection ischemic and hypoxic postconditioning [ 114 , 116 ]. Recent studies show that Cx43 HCs in cardiomyocyte mitochondria interact with ATP-sensitive potassium channels (mKATP) and protect cardiomyocytes against hypoxia/ischemia stress [ 117 , 118 ]. In contrast to the cardioprotection, mitochondrial Cx43 HCs facilitate mitochondrial Ca 2+ entry and may trigger permeability transition and cell injury/death by using connexin-targeting peptides interacting with extracellular (Gap26) and intracellular (Gap19, RRNYRRNY) Cx43 domains [ 119 , 120 ], indicating a detrimental role of Cx43 HCs in cardiomyocytes.…”