Caveolin and GLT‐1 gene expression is reciprocally regulated in primary astrocytes: Association of GLT‐1 with non‐caveolar lipid rafts

Abstract

Caveolae represent membrane microdomains acting as integrators of cellular signaling and functional processes. Caveolins are involved in the biogenesis of caveolae and regulate the activity of caveolae-associated proteins. Although caveolin proteins are found in the CNS, the regulation of caveolins in neural cells is poorly described. In the present study, we investigated different modes and mechanisms of caveolin gene regulation in primary rat astrocytes. We demonstrated that activation of cAMP-dependent signaling pathways led to a marked reduction in protein levels of caveolin-1/-2 in cortical astrocytes. Application of transforming growth factor-alpha (TGF-alpha) also resulted in a decrease of caveolin-1/-2 expression. Decreased caveolin protein levels were mirrored by diminished caveolin gene transcription. The repressive effect of TGF-alpha on caveolin-1 expression was MAP kinase-independent and partly mediated through the PI3-kinase pathway. Further downstream, inhibition of histone deacetylases abrogated TGF-alpha effects, suggesting that chromatin remodeling processes could contribute to caveolin-1 repression. Intriguingly, alterations of caveolin gene expression in response to cAMP or TGF-alpha coincided with reciprocal and brain-region specific changes in glial glutamate transporter GLT-1 expression. The reciprocal regulation of caveolin-1 and GLT-1 expression might be gated through a common PI3-kinase dependent pathway triggered by TGF-alpha. Finally, we showed that GLT-1 is located in non-caveolar lipid rafts of cortical astrocytes. In conclusion, this study highlights the occurrence of the reciprocal regulation of caveolin and GLT-1 expression during processes such as astrocyte differentiation via common signaling pathways. We also provide strong evidence that GLT-1 itself is concentrated in lipid rafts, inferring an important role for glial glutamate transporter function.

Mutual effects of caveolin and nerve growth factor signaling in pig oligodendrocytes

“…The level of caveolin does not necessarily equate with caveolae, and caveolae are not identical with lipid rafts, which never invaginate (Boyanapalli et al, 2005;Head and Insel., 2006). Furthermore, caveolin and eventually caveolae might undergo a spatial and/or temporal regulation (Masserini et al, 1999;Mikol et al, 2002;Zschocke et al, 2005). For the first time, we could demonstrate that caveolae-like invaginations are present at or next to the oligodendroglial plasma membrane.…”

Caveolin expression changes in the neurovascular unit after juvenile traumatic brain injury: Signs of blood–brain barrier healing?

“…However, the changes in pi-eNOS expression are independent of cav-1 and cav-3 expression, thus questioning a role of caveolins in a putative inhibition of eNOS activation and excess release of NO following jTBI. Interestingly, the changes of the level of expression of cav-1 in astrocyte cultures were associated with opposite changes in expression of the glutamate transporter GLT1 (Zschocke et al, 2005, Gonzalez et al, 2007). The application of transforming growth factor-alpha (TGF-α) induced a decrease of cav-1 and an increase of GLT1 (Zschocke et al, 2005, Gonzalez et al, 2007).…”

“…Interestingly, the changes of the level of expression of cav-1 in astrocyte cultures were associated with opposite changes in expression of the glutamate transporter GLT1 (Zschocke et al, 2005, Gonzalez et al, 2007). The application of transforming growth factor-alpha (TGF-α) induced a decrease of cav-1 and an increase of GLT1 (Zschocke et al, 2005, Gonzalez et al, 2007). Increase of cav-1 expression in the astrocyte may, therefore, participate to the mechanism producing a downregulation of GLT1 in the astroglia.…”

Seladin-1/DHCR24 Is Neuroprotective by Associating EAAT2 Glutamate Transporter to Lipid Rafts in Experimental Stroke

“…Alternatively, a reduction in seladin-1/DHCR24 can alter the distribution of EAAT2, a glutamate transporter primarily localized on astrocytic processes. This transporter, which is responsible for ≤90% of all glutamate transport in adult tissue, 10 requires to be associated to lipid rafts to carry out an adequate glutamate uptake, 11,12 thereby decreasing excitotoxicity after ischemia. All in all, a deficit in seladin-1/DHCR24 may affect the response to ischemia through the stress or cholesterol functions of seladin-1/ DHCR24.…”