Abstract
Changes in GABAergic inhibition occur during physiological processes, during response to drugs and in various pathologies. These changes can be achieved through direct allosteric modifications at the γ-amino butyric acid (GABA) type A (GABAA) receptor protein level, or by altering the synthesis, trafficking and stability of the receptor. Neurosteroids (NSs) and protein kinase C (PKC) are potent modulators of GABAA receptors and their effects are presumably intermingled, even though evidence for this hypothesis is only partially explored. However, several PKC isoforms are able to phosphorylate the GABAA receptor, producing different functional effects. We focused on the ε isoform, that has been correlated to the sensitivity of the GABAA receptor to allosteric modulators and whose expression may be regulated in peripheral sensory neurons by NSs. The cross-talk between PKC-ε and NSs, leading to changes in GABAA receptor functionality, is considered and discussed in this perspective.
Highlights
GABAA receptors are fundamental for fast synaptic inhibition in the brain
Recent studies showed that Protein kinase C (PKC)-ε action depends on the phosphorylation of the GABAA receptor at the level of Ser327 of the γ2 subunit (Qi et al, 2007), in turn regulating the response of the receptors to allosteric modulators
Allo did not change PKC-ε expression under basal conditions, but was significantly upregulated in dorsal root ganglia (DRG) neurons exposed to the culture medium from Allo-treated Schwann cells (Figure 1C). These findings suggest that Allo-treated Schwann cells can release one or more factors able to modulate PKC-ε expression in DRG neurons
Summary
GABAA receptors are fundamental for fast synaptic inhibition in the brain. Given the role of these receptors in synaptic transmission, all the mechanisms that regulate their activity are of primary importance. Kinases represent a superfamily of isoenzymes that, through protein phosphorylation, regulate several cellular processes, including proliferation, differentiation, tumorigenesis, cytoskeletal remodeling, receptor function and synaptic transmission modulation (Battaini, 2001). This superfamily comprises the protein kinase (PK) A, G and C, which are serine/threonine phosphotransferases. Protein kinase C (PKC) is one of the most significant kinases for GABAA receptor modulation. Phosphorylation of the receptor can produce different effects, ranging from enhancement to inhibition of protein function, depending on the subtype of subunit targeted and on the location of the sites being phosphorylated (Moss and Smart, 1996). The differences among PKC isoforms contribute to the large range of functions they may perform
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