TRPV1型
门控
化学
生物物理学
离子通道
瞬时受体电位通道
突变
突变
细胞生物学
生物化学
受体
生物
基因
作者
Jörg Grandl,Sung Eun Kim,Valerie Uzzell,Badry Bursulaya,Matt Petrus,Michael Bandell,Ardem Patapoutian
摘要
TRPV1 is a member of the family of temperature-activated transient receptor potential ion channels. This study identifies mutations in the outer pore region of TRPV1 that impair temperature activation by ablating long channel openings. TRPV1 is the founding and best-studied member of the family of temperature-activated transient receptor potential ion channels (thermoTRPs). Voltage, chemicals and heat allosterically gate TRPV1. Molecular determinants of TRPV1 activation by capsaicin, allicin, acid, ammonia and voltage have been identified. However, the structures and mechanisms mediating TRPV1's pronounced temperature sensitivity remain unclear. Recent studies of the related channel TRPV3 identified residues in the pore region that are required for heat activation. We used both random and targeted mutagenesis screens of rat TRPV1 and identified point mutations in the outer pore region that specifically impair temperature activation. Single-channel analysis indicated that TRPV1 mutations disrupted heat sensitivity by ablating long channel openings, which are part of the temperature-gating pathway. We propose that sequential occupancy of short and long open states on activation provides a mechanism for enhancing temperature sensitivity. Our results suggest that the outer pore is important for the heat sensitivity of thermoTRPs.
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