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	Figure 1. Activation of K2P4.1 and K2P10.1 by monoterpenes. (A) Activation of K2P4.1 and K2P10.1. Oocyte membrane potential was held at −80 mV and pulsed to +25 mV for 75 ms with 5 s interpulse intervals. All MTs were applied at the same concentration (0.3 mM), and currents were measured after 4 min (mean ± S.E., n = 5–10). Polar area (Å2) and octanol–water partition coefficient (logP) prediction (XLogP3) were obtained from PubChem (Kim et al., 2016). 2D structures and the coordinates for the 3D structures of the terpenes were obtained from ChemSpider. 3D models were performed with the UCSF Chimera package (Pettersen et al., 2004). Oxygen molecules are colored red. The dashed line represents no change from the initial current. Inset- currents of a representative oocyte expressing K2P10.1 before, during and after thymol application. (B) Currents at 60 mV before (in red) and during (in blue) application of carvacrol (i–iii) or arachidonic acid (AA) (iv), on K2P2,1 (i, iv), K2P4.1 (ii), and K2P10.1 (iii) (C). Fraction of voltage-dependent current (in %) before (black) and after (gray) application of 0.3 mM carvacrol or arachidonic acid (AA, 100 µM). A fit of the current (at 60 mV) to an exponential decay slope was used to identify the initial current (mean ± S.E., n = 6–9).
	Figure 2. Carvacrol and cinnamaldehyde robustly activate K2P5.1. (A) Activation of K2P5.1 by monoterpenes. Oocyte membrane potential was held at −80mV and pulsed to +25 mV for 75 ms with 5 s interpulse intervals. All MTs were applied at the same concentration (0.3 mM), and currents were measured after 5 min of incubation (mean ± S.E., n = 6–10). (B) Time course for activation by 0.3 mM carvacrol and 0.3 mM cinnamaldehyde for representative oocytes expressing K2P5.1 channels. Currents were measured as in (A). (C) Carvacrol dose-response for K2P5.1 channels (mean ± S.E., n = 5–8) (EC50 = 0.13 ± 0.05 mM). (D) Cinnamaldehyde dose–response for K2P5.1 channels (mean ± S.E., n = 5–8) (EC50 = 0.11 ± 0.07 mM). Currents were measured at 25 mV, as in (A), after incubation for 5 min. *p ≤ 0.05, **p ≤ 0.01.
	Figure 3. K2P17.1 and K2P18.1 are activated by monoterpenes. (A), (B) Activation of K2P17.1 (A) and K2P18.1 (B) by monoterpenes. Oocyte membrane potential was held at −80 mV and pulsed to +25 mV for 75 ms with 5 s interpulse intervals. All MTs were applied at the concentration of 0.3 mM, and currents were measured 4 min after application of the indicated monoterpene (mean ± S.E., n = 5–10). Insets: currents of representative oocytes expressing K2P17.1 (A) and K2P18.1 (B) during application of 0.3 mM carvacrol. (C) Fraction of voltage-dependent (VD) current (in %) under control conditions and after application of 0.3 mM carvacrol for three channel types, as indicated. Oocytes were held at −80mV, and currents were measured at 30 mV. A fit of the results to an exponential decay slope was used to identify the initial current (mean ± S.E., n = 6–9). *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, ns, not significant.
	Figure 4. The effect of monoterpenes on acid-sensitive K2P channels. (A) Inhibition of K2P3,1 and K2P9.1 currents. Currents were measured before and after 2 in incubation with the indicated MT (mean ± S.E., n = 5–10). All MTs were applied at a concentration of 0.3 mM. (B) Normalized currents during 0.3 mM thymol application for representative oocytes expressing either K2P2.1, K2P3.1, and K2P9.1. (C) The time constant (τ) of current changes during the application of thymol at different concentrations for K2P2.1 or K2P3.1 (mean ± S.E., n = 6–10). *p ≤ 0.05.
	Figure 5. Inhibition of K2P3.1 by carvone. (A) Current–voltage relationship of a representative oocyte expressing K2P2.1, before and after application of 1mM carvone. (B) The current of a representative oocyte expressing K2P3.1 during incubation with 1 mM carvone. Oocyte membrane potential was held at −80 mV and pulsed to +25 mV for 75 ms with 1 s interpulse intervals. (C) Carvone dose–response for K2P3.1 channels (mean ± S.E., n = 6–10) (Kinhibition = 0.90 ± 0.16 mM). (D) Currents of a representative oocyte expressing K2P3.1 channels before and during incubation with 1 mM carvone at 20 mM potassium at the bath. The oocyte was held at −80 mV, then at −135 mV for 30 ms, and then pulsed from −150 mV to 60 mV in 15 mV intervals. The dashed line represents zero current. (E) Currents at 60 mV of a representative oocyte before and during incubation with 1 mM carvone. Currents were normalized to the initial current. A fit of the results to an exponential decay slope was used to identify the initial current. (F) Tail analysis of currents before and during incubation with 1 mM carvone at external potassium concentration of 100 mM (mean ± S.E., n = 6). For each oocyte, currents were normalized to the current at −105 mV.
	Figure 6. The effect of external K+ on the inhibition of the voltage-dependent current in K2P3.1. (A, B) Steady-state current–voltage relationships for oocytes expressing K2P3.1 at four external potassium concentrations (0, 4, 20, and 100 mM) under control conditions (A) or after incubation with 1 mM carvone (B). Oocytes were held at −80 mV, pulsed to −135 mV for 30 ms, and then pulsed from −150 mV to 60 mV in 15 mV voltage intervals (mean ± S.E., n = 6–9). (C) The fraction of inhibited current due to carvone application of the total current (Total) and its components: the voltage-independent (VI) and the voltage-dependent (VD) currents. Currents at 60 mV were tested at three external potassium concentrations (4, 20, and 100 mM) (mean ± S.E., n = 6–9). (D–G) Current–voltage relationships for oocytes expressing K2P3.1 channels at three different external potassium concentrations, as indicated (mean ± S.E., n = 6–9). Currents were measured as in (A). The voltage-independent (D, E) and the voltage-dependent (F, G) fractions of the current were calculated as in Figure 1C and are presented individually. Measurements were performed before (D, F) and after (E, G) application of 1 mM carvone. *p ≤ 0.05, ns, not significant.

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