Internalization of GABAA receptors in HEK293 cells
Başlık çevirisi mevcut değil.
- Tez No: 403027
- Danışmanlar: Belirtilmemiş.
- Tez Türü: Doktora
- Konular: Mikrobiyoloji, Microbiology
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2001
- Dil: İngilizce
- Üniversite: Baylor College Of Medıcıne-Houston-Texas
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Belirtilmemiş.
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: Belirtilmemiş.
Özet
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Özet (Çeviri)
Adaptive changes involving behavior and the nervous system help organisms cope with their environment and, thus, enhance their survival capacity. In contrast, changes that limit the homeostatic power of the organism are maladaptive which are frequently found to be either the cause or the effect of diseases. At the cellular level, complex systems of synaptic neurotransmission are frequently found at the heart of these changes. GABAa receptors'are the site of fast inhibitory neurotransmission in the CNS. Most nerve cells are innervated by GABAergic neurons, and have GABA receptors. The important role of GABAergic neurotransmission in neuronal processing is evidently demonstrated by the action of many psychoactive drugs exerting their effects via GABAa receptors. This action implicates them to have a role in psychiatric disorders such as anxiety, panic and mood disorders, alcoholism, insomnia, and epilepsy. Intracellular traffıcking may be an important cellular control mechanism for the formation and maintenance of GABAergic synapses and/or their plasticity. This information is also useful in understanding pathologies where GABAergic neurotransmission is directly or indirectly involved. The endocytosis of GABAa receptors was investigated in HEK293 cells expressing receptor al (32- and aip2y2-subunit combinations. Main questions involved the kinetics, regulation and mechanism of cellular events underlying GABAa receptor internalization. For measurement of internalized receptors by radioimmunoassay or immunofluorescence, a triple c-myc epitope was introduced into the amino-terminus of the p2 subunit. As an independent approach to avoid possible pitfall of antibody-triggered internalization, an assay based on biotin inaccessibility was used for al subunits. GABAa aip2- and aip2y2-subunit receptors internalized with a t\a of 5.5 min at 37°C. With both subunit combinations, phorbol 12-myristate-3-acetate enhanced internalization by nearly 100%. Treatment of the cells with hypertonic sucrose prevented both the basal and phorbol ester-induced endocytosis of GABAa receptors. In addition to hypertonic sucrose treatment, acidification of the cytosol also blocked basal level of GABAa receptor endocytesis. GF 109203X, an inhibitor of protein kinase C, blocked the stimulation by phorbol ester but had no detectable effect on basal receptor endocytosis. Coexpression with a dominant-negative mutant of dynamin (K44A) led to a 100% enhancement of GABAa receptor internalization, while the endocytosis of (32-adrenergic receptors was completely prevented. Furthermore, coexpression of N272 dynamin did not affect the basal and PMA-induced endocytosis of aip2y2-subunit receptors. Cholesterol-perturbing drugs including fılipin and methyl-P-cyclodextrin were used to test the role of caveolae pathway in GABAa receptor endocytosis and they produced no appreciable effect. Altogether, these results indicate that the endocytosis of GABAa receptor ocip2-and aip2y2-subunit combinations in HEK293 cells is constitutive, not requiring its ligand for internalization. In addition, we found that internalization of GABAa receptors are positively modulated by activation of PKC in y subunit-independent manner, suggesting that it is open to regulation by knovvn intracellular signaling pathvvays. Lastly, since GABAa receptor endocytosis in HEK293 cells was not prevented by coexpression of the K44A dominant-negative mutant of dynamin and by the cholesterol-perturbing drugs, we concluded that this process follows a clathrin-independent pathway, excluding clathrin-dependent and caveolae pathways. Studying kinetics, regulation and mechanism of cellular events underlying GABAa receptor trafficking not only help us understand GABAa receptor behavior, but also provide a generalization point for the cellular mechanisms of adaptation in physiological, pathological, and pharmacological senses.
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