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An Unorthodox Mechanism Underlying Voltage Sensitivity of TRPV1 Ion Channel

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An Unorthodox Mechanism Underlying Voltage Sensitivity of TRPV1 Ion Channel bioRxiv preprint doi: https://doi.org/10.1101/2020.01.04.894980; this version posted January 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 An unorthodox mechanism underlying voltage sensitivity of TRPV1 ion channel 2 Fan Yang1¶,2, Lizhen Xu1, Bo Hyun Lee2, Xian Xiao2,3, Vladimir Yarov-Yarovoy2 and 3 Jie Zheng2¶ 4 1Department of Biophysics and Kidney Disease Center, First Affiliated Hospital, 5 Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, 6 Zhejiang University School of Medicine, Hangzhou 310058, China. 2Department of 7 Physiology and Membrane Biology, University of California, Davis, California 95616, 8 USA. 3Institute for Basic Medical Sciences, Westlake Institute for Advanced Study, 9 Westlake University, Shilongshan Road No. 18, Xihu District, Hangzhou 310064, 10 Zhejiang Province, China. 11 ¶ Correspondence and requests for materials should be addressed to F.Y. (email: 12 [email protected]) or J.Z. (email: [email protected]) 13 14 Abstract 15 While the capsaicin receptor TRPV1 channel is a polymodal nociceptor for heat, 16 capsaicin, and proton, the channel’s responses to each of these stimuli are 17 profoundly regulated by membrane potential, damping or even prohibiting its 18 response at negative voltages and amplifying its response at positive voltages. 19 Though voltage sensitivity plays an important role is shaping pain responses, 20 how voltage regulates TRPV1 activation remains unknown. Here we showed that 21 the voltage sensitivity of TRPV1 does not originate from the S4 segment like 22 classic voltage-gated ion channels; instead, outer pore acidic residues directly 23 partake in voltage-sensitive activation, with their negative charges collectively 24 constituting the observed gating charges. Voltage-sensitive outer pore movement 25 is titratable by extracellular pH and is allosterically coupled to channel 26 activation, likely by influencing the upper gate in the ion selectivity 27 filter. Elucidating this unorthodox voltage-gating process provides a mechanistic 28 foundation for understanding polymodal gating and opens the door to novel 29 approaches regulating channel activity for pain managements. 30 31 When the lipid bilayer emerged to enclose living cells more than three billion years 32 ago1, this diffusion barrier between cytoplasmic milieu and external environment 33 allowed the establishment of transmembrane ion concentration gradients, which in 34 turn yielded a transmembrane electric potential. Such a membrane potential (Vm) has 35 been widely utilized in cellular signaling: voltage-gated ion channels alter Vm to elicit 36 electric signals for rapid communications2,3; voltage-sensitive enzymes, e.g., Ci-VSP4, 37 couple changes in Vm to the regulation of enzymatic activities and intracellular 38 signaling. For these “classic” voltage-sensing proteins, high sensitivity to voltage (5- 39 fold/mV) has been attributed to a conserved, densely charged “voltage-sensor” 40 domain in the transmembrane region5. Other membrane proteins—including G 41 protein-coupled receptors6, ion channels and transporters7—have also evolved to take 42 cues from Vm to perform their biological functions. Understanding the origin and 43 operation of voltage sensitivity in these membrane proteins is of fundamental 44 importance. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.01.04.894980; this version posted January 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 45 Transient receptor potential vanilloid 1 (TRPV1) channel, a polymodal nociceptor in 46 higher species8, is a good representative of the non-classic voltage-sensitive 47 membrane proteins. TRPV1 is activated by noxious heat above 40°C9, however, its 48 response to heat at depolarized Vm is markedly larger than that at the resting Vm even 49 when the driving force for its non-selective cation current is equal in magnitude (Fig. 50 1a). Similarly, TRPV1’s responses to capsaicin and proton—which elicits spiciness 51 sensation9 and the sustained phase of pain sensation10, respectively—are also 52 substantially asymmetrical (Fig. 1b). Tuning of TRPV1’s nociceptive sensitivity by 53 Vm is a highly dynamic process occurring at human body temperature, with the range 54 of voltage dependence (reflected by the conductance-voltage, or G-V, relationship) 55 shifting over a more than 200 mV range in the presence of an activation stimulus11 56 (Fig. 1c). Dynamic voltage sensitivity makes TRPV1 more sensitive to noxious 57 stimuli when its host sensory neuron has been previously excited (primed) or 58 damaged, a general feature for nociception known as hyperalgesia12. On the flip side, 59 membrane hyperpolarization is expected to inhibit pain responses, offering 60 opportunities for novel clinical intervention. Despite its physiological significance, 61 how TRPV1 senses Vm remains largely elusive. 62 TRPV1 belongs to the voltage-gated-like (VGL) ion channel superfamily (Fig. 1d)13, 63 for which three voltage-sensing mechanisms have been established. For voltage-gated 64 potassium (Kv), sodium (Nav) and calcium (Cav) channels (blue sections in Fig. 1d), 65 multiple regularly spaced basic residues on the transmembrane S4 helix enable it to 14 66 move in response to Vm changes . For two-pore domain potassium channels (K2P) 67 without a voltage-sensor domain (green section in Fig. 1d), permeant cations have 68 been proposed to bestow voltage sensitivity15. For inward-rectifier potassium channels 69 (Kir) (purple section in Fig. 1d), voltage-dependent pore block by endogenous 70 polyamines and Mg2+ ions introduces voltage sensitivity16. These three mechanisms 71 are applicable to about three-fourth of the VGL superfamily; voltage-sensing is less 72 understood for a significant portion of the family (red section) that is composed of 73 cellular sensor TRP channels including TRPV1. Our study began by determining 74 whether TRPV1 employs one of these three known mechanisms or a new mechanism 75 to detect Vm. 76 Characterizing TRPV1’s voltage sensitivity 77 A fundamental parameter for voltage sensitivity is the total charge movement, q, 78 which determines the steepness of voltage response5. TRPV1 is known to exhibit 79 shallow voltage dependence11. By fitting a Boltzmann function to the G-V curve of 80 mouse TRPV1 recorded in HEK293 cells (Fig. 1c), the apparent q was estimated to be 81 0.72 ± 0.05 e0 (n = 4). Applying this approach to Kv channels yielded an apparent q of 17 82 5.3 e0 . However, it is well known that fitting the shape of G-V curves could yield an 83 under-estimate of q, for example, when there are multiple voltage-dependent closed 84 states that the channel may traverse before reaching the open state17-19. Indeed, the 85 total gating charge of Kv, K2P and Kir channels are about 13 e0, 2.2 e0 and 2.2 e0, 86 respectively15,16,18. 87 The relatively weak voltage sensitivity of TRPV1 precluded direct measurement of q 88 from gating current. Alternatively, the limiting-slope method20,21 is a classic approach 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.01.04.894980; this version posted January 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 89 to estimate q, for which voltage dependence was measured at low open probabilities. 90 However, the voltage-driven transition of TRPV1 is allosterically coupled to 91 activation gating22, with the channel open probability approaching a stable level at 92 deep hyperpolarization (Fig. 1e and Extended Data Fig. 1) that reflected the 93 equilibrium of activation gate between the closed and open state23. To better estimate 94 q, we first calculated the derivative of the mean log open probability with respect to 95 voltage and fitted the Boltzmann smoothing function of voltage dependence of mean 96 log open probability (see Methods for details) (Fig. 1f), as was previously performed 97 on the allosteric large conductance calcium activated potassium (BK) channels23. This 98 approach yielded an estimated q of 0.93 e0, which is 30% larger than that measured 99 from fitting a Boltzmann function to the G-V curve (0.72 e0), yet much smaller than 23,24 100 that of BK channels (2.62 e0) . To estimate the potential deviation of the gating 101 charge estimate from its true value, we simulated the voltage sensitivity of TRPV1 102 open probability based on a simple allosteric scheme (Extended Data Figure 2a). With 103 the hypothetical gating charge value set to span a wide range from 1.0 e0 to 13.0 e0, 104 our estimations (Extended Data Figure 2b to 2e, dotted red curves) were close to the 105 true value, with deviations ranging from 3.3% to 5.3% (Extended Data Figure 2f). 106 When the method was applied to BK channels, for which total gating charge could be 107 directly measured from the gating current, an underestimation of 7.7% was seen23,24. 108 TRPV1 S4 does not serve as a voltage sensor 109 The S1-to-S4 domain of TRPV1 channels, like its counterpart in Kv channels25, forms 110 a compact domain surrounding the channel pore26,27. In Kv channels, this domain 111 serves as the voltage sensor28. To test whether TRPV1 also relies on the S1-to-S4 112 domain to sense Vm, we first compared the S4 sequences (Fig. 2a). The Kv channel 113 S4 segments contain seven regularly spaced charged residues. The corresponding 114 residues in TRPV1 are all uncharged except for R558, which matches to R6 of Kv at 115 the end of S4 thought to be insignificant for voltage-sensing28. To test for a potential 116 contribution of R558 to voltage sensitivity, we mutated this residue to leucine.
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