Abstract
Post-translational modifications of connexins play an important role in the regulation of gap junction and hemichannel permeability. The prerequisite for the formation of functional gap junction channels is the assembly of connexin proteins into hemichannels and their insertion into the membrane. Hemichannels can affect cellular processes by enabling the passage of signaling molecules between the intracellular and extracellular space. For the intercellular communication hemichannels from one cell have to dock to its counterparts on the opposing membrane of an adjacent cell to allow the transmission of signals via gap junctions from one cell to the other. The controlled opening of hemichannels and gating properties of complete gap junctions can be regulated via post-translational modifications of connexins. Not only channel gating, but also connexin trafficking and assembly into hemichannels can be affected by post-translational changes. Recent investigations have shown that connexins can be modified by phosphorylation/dephosphorylation, redox-related changes including effects of nitric oxide (NO), hydrogen sulfide (H2S) or carbon monoxide (CO), acetylation, methylation or ubiquitination. Most of the connexin isoforms are known to be phosphorylated, e.g. Cx43, one of the most studied connexin at all, has 21 reported phosphorylation sites. In this review, we provide an overview about the current knowledge and relevant research of responsible kinases, connexin phosphorylation sites and reported effects on gap junction and hemichannel regulation. Regarding the effects of oxidants we discuss the role of NO in different cell types and tissues and recent studies about modifications of connexins by CO and H2S.
Highlights
Connexins (Cxs), a protein family with 21 members in humans, share some important functional and structural characteristics
We provide an overview about the current knowledge and relevant research of responsible kinases, connexin phosphorylation sites and reported effects on gap junction and hemichannel regulation
The formation of functional gap junction (GJ) does not seem to require Cx phosphorylation since truncated Cx43 lacking most of the cytoplasmic C-terminal region were still able to form functional GJs, albeit with different conductance than those formed by wild-type Cx43 [15, 16]
Summary
Connexins (Cxs), a protein family with 21 members in humans, share some important functional and structural characteristics. Internalization and degradation are highly associated with phosphorylation/dephosphorylation events and can be triggered by a variety of stimuli (e.g., growth factors, extracellular matrix interactions, ischemia, wounding, inflammation, etc.) [9, 19] These phosphorylation changes are related with changes in the gap junction intercellular communication (GJIC) and may be necessary for normal cell cycling [19]. Phosphorylation of connexins by serine/threonine kinases and its effect on GJs cAMP-dependent protein kinase A (PKA) In a variety of cell populations, an increase of cAMP concentration is correlated with an upregulation of GJIC, but there are reports showing that cAMP increases had an inhibitory effect or no effects upon GJIC [27]. In vivo phosphorylation of Cx50 (Ser395) by PKA in chicken lens has been shown to promote dye
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