S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Biomedical Sciences (대학원 의과학과) Theses (Ph.D. / Sc.D._의과학과)
A novel direct activation mechanism of TRPC4 and TRPC5 channels by selective Gαi subunits
Gαi 아형 단백질에 의한 TRPC4와 TRPC5 이온통로의 활성화 기전에 관한 연구
- 의과대학 의과학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 의과학과 의과학 전공, 2012. 8. 서인석.
- The Transient Receptor Potential Canonical (TRPC) channels function as non-selective, Ca2+-permeable channels and mediate numerous cellular functions. It is commonly assumed that TRPC channels are activated by stimulation of Gαq-PLC-coupled receptors. However, whether the Gαq-PLC pathway is the main regulator of TRPC4/5 channels and how other Gα proteins may regulate these channels are poorly understood. We previously reported that TRPC4/TRPC5 can be activated by Gαi. In the current work, we found that Gαi subunits, rather than Gαq, are the primary and direct activators of TRPC4 and TRPC5. We report a novel molecular mechanism in which TRPC4 is activated by several Gαi subunits, most prominently by Gαi2, and TRPC5 is activated primarily by Gαi3. Activation of Gαi by the muscarinic M2 receptors or expression of the constitutively active Gαi mutants equally and fully activates the channels. Moreover, both TRPC4 and TRPC5 are activated by direct interaction of their conserved C-terminal SEC14-like and spectrin-type domains (SESTD) with the Gαi subunits. Two amino acids (lysine 715 and arginine 716) of the TRPC4 C-terminus were identified by structural modeling as mediating the interaction with Gαi2. These findings indicate an essential role of Gαi proteins as novel activators for TRPC4/5 and reveal the molecular mechanism by which G proteins activate the channels.
* This work is published in The Journal of biological chemistry (2012