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신경세포 시냅스에서 Shank2, Homer 1b와 PLC-β3의 신호전달 복합체 형성
황종익,신금주,류성호,서판길 한국뇌학회 2001 한국뇌학회지 Vol.1 No.2
포스포리파아제 C-베타(phospholipase C-β: PLC-β) 동위효소는 G-proteins-coupled receptors(GPCR)와 그의 신호전달 매개체인 heterotrimeric G proteins에 의해 활성화된다. PLC-β는 효소적 활성에 필요한 영역 외에 카르복시 말단에 PSD-95/Dlg/ZO-1 (PDZ)-binding motif를 가진다. 이 motif는 PLC-β가 PDZ domain을 가진 단백질들과 결합함으로써 GPCR 매개 신호전달에서 특이적인 역할을 수행할 가능성을 제시한다. 이에 본 연구자들은 효모 two-hybrid assay를 통하여 Shank2가 PLC-β3와 결합함을 이전에 확인하였다. 본 연구에서는, 면역침전반응을 통해 두 단백질의 결합은 PLC-β3의 카르복시 말단의 PDZ-binding motif를 통하여 이루어짐을 확인하였고 신경세포의 시냅스에서 mGluR1 및 IP3 수용체와 결합하는 Homer 1b 와 Shank2가 PLC-β3와 함께 위치하는 것을 발견하였다. 이러한 결과는 전자현미경을 이용하여 Homer 1b와 Shank2가 위치하는 PSD 영역에서 PLC-β3가 존재함을 확인하고 mGluR1과 Shank2, Homer 1b, PLC-β3가 해마와 소뇌의 많은 부분에서 동시에 발현되는 것을 확인함으로써 다시 한번 입증되었다. 결과를 종합해 볼 때, 이들 세 단백질은 같은 신경세포의 시냅스에서 발현되어 복합체를 형성함으로써 mGluR1에 의해 매개되는 신호전달을 보다 효율적으로 수행할 수 있을 것으로 예상된다. Phospholipase C-β isotypes activated by G protein-coupled receptors (GPCR) and heterotrimeric G proteins carry a PSD-95/Dlg/ZO-1 (PDZ)-binding motif in their carboxyl terminus. This motif may enable PLC-β isotypes to play specific roles in GPCR signaling through interacting with PDZ-containing proteins. We identified Shank2 as a PLC-β3 binding protein, using yeast two-hybrid system in the previous study, and here we characterized the binding of PLC-β3 with Shank2. Immunoprecipitation study showed that Shank2 interacts with PDZ-binding motif of PLC-β3. Moreover, PLC-β3 was colocalized with Shank2 and Homer 1b that interacts with mGluR1 and IP3 receptor on the synapse of primary-cultured neuronal cells. Immunogold EM also showed that PLC-β3 immunoreactivity was detected at the PSD of the CA1 pyramidal neurons. In several regions of hippocampus and cerebellum, the expression pattern of Shank2 was similar to that of mGluR1, Homer 1b, and PLC-β3. These results suggest that PLC-β3, Shank2, and Homer 1b may act as active intermediates in mGluR1-mediated signal transduction by forming signaling complex in neuronal synapses.
Phospholipase C-β3 Mediates the Thrombin-induced Ca2+ Response in Glial Cells
Pann-Ghill Suh,Jong-Ik Hwang,Kum-Joo Shin,Yong-Seok Oh,Jung-Woong Choi,이지원,Daesoo Kim,Kwon-Soo Ha,신희섭,Sung Ho Ryu 한국분자세포생물학회 2005 Molecules and cells Vol.19 No.3
Phospholipase C-β (PLC-β) hydrolyses phosphatidylinositol 4,5-bisphosphate and generates inositol 1,4,5-trisphosphate in response to activation of various G protein-coupled receptors (GPCRs). Using glial cells from knock-out mice lacking either PLC-β1 [PLC-β1 (-/-)] or PLC-β3 [PLC-β3 (-/-)], we examined which isotype of PLC-β participated in the cellular signaling events triggered by thrombin. Generation of inositol phosphates (IPs) was enhanced by thrombin in PLC- β1 (-/-) cells, but was negligible in PLC-β3 (-/-) cells. Expression of PLC-β3 in PLC-β3 (-/-) cells resulted in an increase in pertussis toxin (PTx)-sensitive IPs in response to thrombin as well as to PAR1-specific peptide, while expression of PLC-β1 in PLC-β1 (-/-) cells did not have any effect on IP generation. The thrombin-induced [Ca2+]i increase was delayed and attenuated in PLC-β3 (-/-) cells, but normal in PLC-β1 (-/-) cells. Pertussis toxin evoked a delayed [Ca2+]i increase in PLC-β3 (-/-) cells as well as in PLC-β1 (-/-) cells. These results suggest that activation of PLC-β3 by pertussis toxin-sensitive G proteins is responsible for the transient [Ca2+]i increase in response to thrombin, whereas the delayed [Ca2+]i increase may be due to activation of some other PLC, such as PLC-β4, acting via PTx-insensitive G proteins.