SHRM4, A PROTEIN INVOLVED IN X-LID, DRIVES GABA B RECEPTORS INTO DENDRITES THROUGH ITS ASSOCIATION WITH THE DYNEIN/DYNACTIN COMPLEX
Tesi di Dottorato
Data di Pubblicazione:
2014
Citazione:
SHRM4, A PROTEIN INVOLVED IN X-LID, DRIVES GABA B RECEPTORS INTO DENDRITES THROUGH ITS ASSOCIATION WITH THE DYNEIN/DYNACTIN COMPLEX / J. Zapata ; tutor: M. Passafaro; Coordinatore: A. Panerai. DIPARTIMENTO DI SCIENZE FARMACOLOGICHE E BIOMOLECOLARI, 2014 Jan 16. 26. ciclo, Anno Accademico 2013. [10.13130/zapata-jonathan_phd2014-01-16].
Abstract:
Mutations in the KIAA1202 gene coding for the Shrm4 protein have been involved in
intellectual disabilities (ID). However, its expression and role in the brain is still unknown.
Our data revealed that Shrm4 is present in both cortical and hippocampal primary cultured
neurons and localizes at the pre- and post-synapse. ShRNA-mediated Shrm4 knock-down
leads to a dramatic reduction in spine density and length. Furthermore, we detected a
significant decrease in the expression level of synaptic markers compared to scrambled
control. Using different biochemical and imaging approaches, we showed that the N-terminal
PDZ domain of Shrm4 interacts directly with the C-terminal tail of GABAB receptor subunit
isoforms 1 (GABAB1) (both GABAB1a and GABAB1b subunits). We observed for the first time
that Shrm4 regulates GABABRs transport in dendrites by modulating its association with the
microtubule-dependent dynein/dynactin motor complex. According to our hypothesis, in vivo
and in vitro Shrm4 knockdown reduces GABAB receptor-mediated K+ currents induced by
baclofen application. These results supported the presence of a trimeric complex, necessary
for the correct targeting of GABAB receptors to dendrites and for its physiological role in
brain transmission. These observations raised evidences that symptoms observed in Shrm4
deficient human patients such as epilectic seizures could arise from reduced level of
functional GABAB receptors.
Tipologia IRIS:
Tesi di dottorato
Keywords:
X-LID ; GABAB receptors ; trafficking ; brain excitability ; dynein/dynactin complex ; microtubule-based motors
Elenco autori:
J. Zapata
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