Temperature-induced opening of TRPV1 ion channel is stabilized by the pore domain

被引:164
作者
Grandl, Joerg [1 ]
Kim, Sung Eun [1 ]
Uzzell, Valerie [1 ]
Bursulaya, Badry [2 ]
Petrus, Matt [2 ]
Bandell, Michael [2 ]
Patapoutian, Ardem [1 ,2 ]
机构
[1] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA
[2] Novartis Res Fdn, Genom Inst, San Diego, CA USA
基金
美国国家卫生研究院;
关键词
CAPSAICIN RECEPTOR; HEAT ACTIVATION; COLD RECEPTOR; THERMOSENSATION; VOLTAGE; SENSITIVITY; SENSATION; STIMULI; THERMODYNAMICS; REVEALS;
D O I
10.1038/nn.2552
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:708 / 714
页数:7
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