Garg P , Gardner A , Garg V , Sanguinetti MC .

R01HL103877 NHLBI NIH HHS , R01 HL103877 NHLBI NIH HHS

	Figure 1. State-independent block of Slo2.1 channels by verapamil and D890. (A) Activation of ISlo2.1 during repetitive pulsing to 0 mV (0.3-s duration, 10-s interpulse interval) by 6 mM NFA under control conditions (i), and after a 10-min equilibration with 100 µM verapamil (ii). (B) Time course of ISlo2.1 in a single oocyte during activation with 6 mM NFA, washout of NFA, incubation with 100 µM verapamil for 10 min, and reapplication of 6 mM NFA in the continued presence of verapamil. The oocyte was clamped at −90 mV and pulsed to 0 mV every 10 s except during the 10-min incubation with verapamil. The notations “i” and “ii” correspond to the currents shown in A. (C and D) External application of 100 µM D890 does not block ISlo2.1. Protocol and notations are the same as noted for A and B. (E) Plot of normalized and mean peak ISlo2.1 induced by 6 mM NFA alone and by 6 mM NFA in the presence of 100 µM verapamil (n = 6; *, P < 0.0001) or D890 (n = 8) after a 10-min pulse-free equilibration period. Error bars indicate mean ± SEM. (F and G) Mean currents (18–25 consecutive sweeps) recorded from inside-out excised macropatches during voltage ramps from +80 to −140 mV. Currents were recorded in the absence (control) and presence of 100 µM verapamil (F) or 100 µM D890 (G). Arrows indicate 0 current level. (H) Time course of E275D ISlo2.1 block by 100 µM verapamil, added to the extracellular solution, measured in response to a train of test pulses applied to +60 mV. Two pulse train protocols are compared. One protocol used 3-s pulses that were applied once every 5 s (open circle, n = 6). The other protocol used 0.3 s pulses that were applied once every 30 s (red circle, n = 6). Currents were normalized to ISlo2.1 measured before drug treatment, and each oocyte was subjected to only one pulse train. Error bars indicate mean ± SEM. (I) Diagram illustrating proposed mechanism of Slo2.1 channel block by verapamil and its quaternary amine derivative D890. Verapamil, but not D890, can cross the cell membrane into the cytoplasm. When applied to the bathing solution of inside/out patches, both compounds can block channels in a state-independent manner, which suggests that the S6 segments do not form a physical barrier to drug entry into the central cavity.
	Figure 2. Molecular determinants for verapamil block of Slo2.1 channels. (A) Amino acid sequence alignment of the pore region of Slo2.1 with other K+ channels. Sequence alignment begins with pore helix (PH) followed by the selectivity filter (SF) and S6 segment. Ser241, Thr242, and residues in S6 of human Slo2.1 that were mutated to Ala are underlined. Mutation of colored residues to Ala caused gain of function (green) or loss of function (blue). P475 in Shaker and E92 in MthK channel are colored red. (B) Bar graph summarizing relative block of ISlo2.1 (Iverapamil/Icontrol) by 15 µM verapamil for WT channels and channels with indicated point mutation. The broken horizontal line indicates Iverapamil/Icontrol value for WT channels. Currents were activated by 1 mM NFA and elicited with 300-ms pulses to 0 mV. Error bars indicate mean ± SEM. (C) Homology model of Slo2.1 pore domain viewed from cytoplasmic side and showing side chains of Ser241 (yellow), Val268 (magenta), and Phe274 (cyan). (D) Concentration-dependent block of WT Slo2.1 channel currents by verapamil. ISlo2.1 activated by 1 mM NFA in the absence (control) and presence of indicated [verapamil]. Pulses were applied to 0 mV for 300 ms. (E) [Verapamil]–response curve for WT and mutant Slo2.1 channels. The IC50 was 14.5 ± 0.6 µM (nH = 1.5 ± 0.1; n = 7) for WT channels, 58.7 ± 9.4 µM (nH = 1.1 ± 0.2, n = 6) for F274T channels activated by 1 mM NFA (red circles), 53.0 ± 2.4 µM (nH = 1.0 ± 0.06, n = 4) for constitutively active F274T channels (blue triangles), and 4.6 ± 2.3 µM (nH = 1.4 ± 0.5, n = 4) for V268A channels (teal circles). Error bars indicate mean ± SEM.
	Figure 3. Mutagenesis scan of S6 segment identifies residues important for normal Slo2.1 channel gating. (A) 33 consecutive residues (Thr252 to Arg284) located in the S6 segment were individually mutated to Ala (native Ala residues were mutated to Cys), and the effect of 1 and 6 mM NFA on ISlo2.1 was quantified at a test potential of 0 mV. Oocytes were injected with 0.2–2 ng cRNA and recorded 1–3 d later (n = 4–6). Five mutations (K256A, I263A, P271A, Q273A, and E275A) caused complete loss of channel function (indicated by the asterisks). (B) Plot of peak currents measured at 0 mV in the absence (black boxes) and presence of 1 mM NFA (red circles) and 6 mM NFA (blue triangles) for the five loss-of-function mutant channels. Mutant channel currents measured in presence of 6 mM NFA were corrected by subtraction of the mean value for endogenous currents activated by 6 NFA in uninjected oocytes. Oocytes were injected with 10 ng of cRNA and incubated for 3–4 d (n = 6–10). The right panel shows the same data plotted on an expanded y axis. Error bars indicate mean ± SEM.
	Figure 4. Intracellular NaCl loading of oocytes activates a robust ISlo2.1 in oocytes expressing WT Slo2.1, but not in oocytes expressing S6 mutant channels that did not respond to NFA treatment. (A) Time course of ISlo2.1 activation induced by leakage of NaCl from recording pipettes in a single oocyte injected with 10 ng WT Slo2.1 cRNA. Currents were elicited with 300-ms pulses applied to 0 mV every 10 s for a total of 5 min, 40 s. The first current (smallest amplitude) was recorded immediately after impalement of the oocyte. The arrow on left indicates 0 current level. (B) Mean time course of ISlo2.1 activation induced by intracellular NaCl loading for cells recorded 3 d after injection with 10 ng WT Slo2.1 cRNA (n = 12) compared with uninjected cells (n = 12) from the same batch of oocytes. Currents were measured at the end of 300-ms pulses applied to 0 mV every 10 s. (C) NaCl loading activates small currents in oocytes expressing K256A, I263A, and Q273A mutant channels. The right panel shows data with an expanded y axis. (D) P271A and E275A mutant channels are not activated by NaCl loading. The right panel shows data with an expanded y axis. Error bars indicate mean ± SEM.
	Figure 5. Western blot analysis of oocytes expressing WT and S6 mutant Slo2.1 channels. (A) Proteins in the biotinylated membrane fraction were separated by SDS-PAGE electrophoresis, and gels were blotted to detect FLAG-tagged Slo2.1. In the top panel, Slo2.1 monomer is represented by a 120-kD band, which is absent in uninjected oocytes. The 130-kD band in the top panel was detected in all lanes and represents nonspecific labeling by the antibody. For the top panel, lanes 1 and 2 were loaded with samples from oocytes injected with 10 and 1 ng WT FLAG-tagged Slo2.1 cRNA, respectively. For all other panels, lanes 1 and 2 represent samples from oocytes injected with 1 and 10 ng WT FLAG-tagged Slo2.1 cRNA, respectively. Na+/K+ ATPase (plasma membrane marker), but not GAPDH (cytosolic marker), was present in this fraction. (B) Western blots for Na+/K+ ATPase and GAPDH from the cytosolic fraction. (C) Comparison of relative surface protein expression and current magnitude for WT and S6 mutant Slo2.1 channels. Western blots in A were quantified by densitometry using the area under the curve method of ImageJ software to correct for background noise, and the nonspecific 130-kD band observed in all lanes, including the uninjected oocytes lane. The ratio of FLAG-tagged Slo2.1 Na+/K+ ATPase band intensities from the same membrane fraction sample was determined for each lane. The relative band intensity of mutant Slo2.1 proteins (cyan bars) were calculated by normalization to the ratio determined for the sample of oocytes injected with 10 ng WT cRNA. Currents were measured at 0 mV after activation with either 1 mM NFA (ISlo2.1NFA, calculated from data plotted in Fig. 3 B) or by intracellular loading with NaCl (ISlo2.1Na, calculated from data plotted in Fig. 4, C and D).
	Figure 6. Slo2.1 channels with hydrophobic substitutions of Glu275 are nonfunctional. The peak magnitude of currents recorded at the end of 0.3-s pulses to 0 mV in response to 1 and 6 mM NFA are plotted as a function of the GES hydrophobicity scale value for free energy transfer from water to membrane (Engelman et al., 1986) for the indicated Glu275 substitution (in single letter code). WT channels are indicated as “E.” ISlo2.1 for E275D channels (“D”) represents constitutive activity (no NFA) in oocytes injected with 1 ng cRNA and recorded after 3 d (n = 5). Currents in WT channels and for all other mutant channels were measured in oocytes 2 d after injection with 10 ng of Slo2.1 cRNA (for WT channels, n = 10; for mutant channels, n = 5). Error bars indicate mean ± SEM.
	Figure 7. A highly conserved mutation in S6, E275D, enhances channel opening probability. (A) Currents recorded from an oocyte expressing E275D Slo2.1 channels without NFA treatment. (B) I-Vt relationship for E275D Slo2.1 channels with [K+]e of 2 and 104 mM (1 ng cRNA/oocyte; 2 d expression; n = 8). (C) G-V relationship for E275D channels calculated from ISlo2.1 recorded from oocytes bathed in K104 solution (n = 4). Data were fitted with a Boltzmann function (smooth curve) to estimate V0.5 (92.4 ± 1.4 mV), z (0.48 ± 0.01 e), and minimum G/Gmax (0.14). (D) Relative amplitudes of instantaneous (Ainst), and the fast (Afast) and slow (Aslow) time-dependent components of E275D ISlo2.1. (E) Time constants for activation of E275D ISlo2.1. For D and E, oocytes were injected with 1 ng cRNA and recorded 2 d later (n = 11). (F) [NFA]–response relationship for E275D Slo2.1 channels. Data were fitted with a logistic equation (smooth curve) to calculate EC50 (192 ± 25 µM) and nH (1.08 ± 0.09, n = 10). (G and H) E275D ISlo2.1 recorded in the same oocyte under control conditions (G) and after further activation by 3 mM NFA (H). Vh was −90 mV and pulses were applied in 20-mV steps to a Vt that ranged from +80 to −140 mV. (I) Mean I-Vt relationships for oocytes expressing E275D Slo2.1 channels (1 d after injection with 0.5 ng cRNA) under control conditions and after treatment with 3 mM NFA (n = 5). (J and K) E275D ISlo2.1 recorded in the same oocyte under control conditions (J) and after further activation by intracellular loading with NaCl (K). Vh was −90 mV and pulses were applied in 20-mV steps to a Vt that ranged from +80 to −140 mV. (L) Mean I-Vt relationships for oocytes expressing E275D Slo2.1 channels (n = 11) under control conditions (1 d after injection with 0.4 ng cRNA) and after NaCl loading (NaCl), and uninjected oocytes (n = 5) before (control) and after NaCl loading (NaCl). Error bars indicate mean ± SEM.
	Figure 8. Intragenic rescue of nonfunctional E275A Slo2.1 was achieved by introducing a charged residue one helical turn away in the S6 segment. Mean I-Vt relationships recorded before (control) and after treatment of oocytes with NFA for E275A/A278E channels (A; n = 5; 5 ng cRNA injected, currents recorded after 4 d), E275A/A278R channels (B; n = 8; 1 ng cRNA injected, currents recorded after 2 d), and E275A/Y279E channels (C; n = 6; 10 ng cRNA injected, currents recorded after 4 d). (D–F) E275A/Q276E channels (D), E275A/L277E channels (E), and E275A/L280E channels (F). For D–F: n = 6; 10 ng cRNA injected, currents recorded after 5 d. Error bars indicate mean ± SEM. (G) Helical wheel plot of S6 segment of Slo2.1 from Pro271 to Arg284. The arrow points to Glu275, R indicates the two residues that when mutated to Glu rescued E275A channel function, and NR indicates the three residues that when mutated to Glu did not rescue E275A channel function. A wheel plot was made using the Wheel.pl program written by D. Armstrong and R. Zidovetzki (http://rzlab.ucr.edu/scripts/wheel/wheel.cgi). Residues are shape- and color-coded to indicate physical properties as follows: circles, uncharged hydrophilic (proportional to the intensity of red color); diamonds, hydrophobic (proportional to the intensity of green color); triangles, acidic; pentagon, basic. (H and I) MthK-based model of the Slo2.1 pore domain (S5-PH-S6) viewed from the intracellular side. Key residues are labeled for one subunit in each panel. Mutation of Ala278 or Tyr279 (H) to Glu rescued function of E275A channels. Mutation of Gln276, Leu277, or Leu280 (I) did not rescue E275A channels.
	Figure 9. Point mutation of S6 residues that face the pore helix exhibit enhanced sensitivity to NFA. (A) Homology model of pore helix and S6 segment of one Slo2.1 subunit highlighting potential residue interactions. (B) Peak outward currents measured at 0 mV in the absence (control) and presence of 1 and 6 mM NFA for channels with point mutations of the native residues in the pore helix (PH) or S6 highlighted in A (n = 5–7). (C–E) ISlo2.1 recorded from oocytes expressing M262A, F258A, and A266G Slo2.1 channels before (control) and after treatment with 0.1 and 1 mM NFA. Arrows indicate 0 current level. (F) [NFA]–response relationships for WT and gain-of-function S6 mutant channels. Data were fitted with a logistic equation (smooth curve). For WT (n = 9), EC50 = 2.1 ± 0.1 mM, nH = 2.4 ± 0.06; for F258A (n = 7): EC50 = 0.4 ± 0.05 mM, nH = 1.2 ± 0.08; for M262A (n = 6), EC50 = 0.66 ± 0.13 mM, nH = 1.4 ± 0.06; for A266G (n = 5), EC50 = 0.38 ± 0.03 mM, nH = 1.2 ± 0.03. Error bars indicate mean ± SEM.
	Figure 10. Substitutions of the pore helix residue Phe240 induce a spectrum of constitutive channel activity. (A) NFA further activates F240L and F240V channels, but not F240C channel currents. Currents were elicited with 300-ms pulses to 0 mV from a Vh of −80 mV. Arrows indicate 0 current level. (B) Relationship between constitutive channel activity of Phe240 mutant channels and hydrophilicity of the introduced residue (indicated by single letter code). Ic-rel for WT (“F”) and mutant channels (n = 4–12) are plotted as a function of solvent parameter (hydrophilicity) values (Levitt, 1976) for the indicated Phe240 substitution. The line represents a linear regression fit of data (adjusted R2 = 0.41). (C) I-Vt relationships for F240C Slo2.1 channel currents measured from oocytes bathed in KCM211 or K104 extracellular solution in the absence and presence of 1 mM NFA (n = 6). (D) I-Vt relationships for WT and F240C Slo2.1 channel currents recorded before and after maximal increase in outward currents induced by NaCl loading from recording pipettes (n = 9). Error bars indicate mean ± SEM.
	Figure 11. Mutation analysis of three residues in the S5 segment predicted to form intrasubunit interactions with the pore helix of Slo2.1. (A) MthK-based homology model of a single Slo2.1 subunit highlighting Phe240 in the pore helix (PH) and three potential interacting residues in the S5 segment. (B) Peak outward ISlo2.1 measured at 0 mV in the absence (control) and presence of 1 and 6 mM NFA for mutant channels with indicated point mutations in S5 (n = 5–7). (C) [NFA]–response relationship for L209T Slo2.1 channels. ISlo2.1 was measured at 0 mV and normalized to the peak current measured in the presence of 3 mM NFA. Data were fitted with a logistic equation (smooth curve). EC50 = 106 ± 9 µM, nH = 1.39 ± 0.12 (n = 6). (D) I-Vt relationships for L209T ISlo2.1 in oocytes bathed in KCM211 and K104 solutions. (E) I-Vt relations for L209T ISlo2.1 before and after treatment with 1 mM NFA (n = 10). (F) I-Vt relationship for L209T ISlo2.1 before and after intracellular NaCl loading. For data presented in C–F, oocytes were injected with 0.7 ng cRNA and currents were recorded 1 d later. Error bars indicate mean ± SEM.
	Figure 12. Screen of several gain-of-function point mutations for the ability to rescue P271A and E275A Slo2.1 channels. (A) Effect of 1 and 6 mM NFA on I-Vt relationships for oocytes expressing WT channels (n = 4). Oocytes were injected with 10 ng cRNA, and currents were recorded 2 d later. (B) I-Vt relationships for uninjected oocytes treated with NFA (n = 9). 1 mM NFA had no effect, but 6 mM NFA activated a relatively small endogenous current. (C–F) I-Vt relationships showing that E275D and R190E, but not F240C or A278R, can rescue P271A channel function (n = 4–7). (G and H) I-Vt relationships showing that R190E (n = 7) and F240C (n = 10) do not rescue E275A channels. For B–H, oocytes were injected with 10 ng cRNA, and currents were recorded after incubation for 2 d (C) or 3–4 d (B and D–H). Error bars indicate mean ± SEM.
	Figure 13. Diagrams illustrating the major structural changes associated with activation gating in Kv compared with changes proposed for Slo2.1 channels. (A and B) Opening of Kv channels requires a voltage-activated outward displacement of the S4 segments and splaying of the inner S6 segments (activation gate) away from the central cavity. Each panel depicts the S4-S6 segments of two diagonally positioned channel subunits. These segments, the pore helices (PH), and the selectivity filter (SF) are labeled in B. In the S4 segments, “+” indicates a basic residue. (C and D) Model of Slo2.1 channel activation. The S6 segments do not form a bundle crossing, and the S4 segments, each with an equal number of basic (+) and acidic (−) residues, do not move in response to voltage. The selectivity filter serves as the activation gate to control the transmembrane flux of K+. Mutation of Phe240 (yellow circles, located at the base of the pore helix) to Cys induces constitutive channel opening, which suggests a key, but mechanistically undefined role for this residue in selectivity filter-mediated gating. The kink in the S6 segment of Slo2.1 represents the approximate position of Pro271 that is located four residues above Glu275 (red circles). Together these residues are proposed to prevent formation of an S6 bundle crossing in Slo2.1. Finally, it is proposed that the selectivity filter gate is allosterically activated by a twisting of S6 segments (green arrows) in response to binding of cytoplasmic Na+ to the C termini of Slo2.1 subunits.

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