Scholl ES , Pirone A , Cox DH , Duncan RK , Jacob MH .

F31 DC010114 NIDCD NIH HHS , P30NS047243 NINDS NIH HHS , F31DC010114 NIDCD NIH HHS , R01DC008802 NIDCD NIH HHS , P30 NS047243 NINDS NIH HHS , R01 DC008802 NIDCD NIH HHS

	Figure 1. α-actinin localizes to olivocochlear postsynaptic sites in sensory hair cells and interacts with SK2 channels. (A–C) Micrographs of fluorescent immunolabeling of E19 chicken hair cells show that SK2 (red, A) and the postsynaptic scaffold protein S-SCAM (red, B) are predominantly concentrated at olivocochlear postsynaptic sites, based on juxtaposition and partial overlap (yellow) with SV2 labeled presynaptic terminal vesicle clusters (green, A and B). α-actinin (red, C) is also enriched at postsynaptic sites, based on co-localization and strong overlap with S-SCAM (green, C). Lower panels: Profiles of pixel intensity peaks show partial overlap of SK2 with SV2 (A) and S-SCAM with SV2 (B), and almost complete overlap of α-actinin with S-SCAM (C). Pixel intensities were measured along a line drawn vertically across the postsynaptic and presynaptic membranes (white lines shown in middle panels). Scale bar = 5μM. (D) Co-precipitation of SK2 channels with α-actinin-1 from E20 chicken cochlea lysates, detected by immunoprecipitating (IP) SK2 and immunoblotting (IB) with an anti-α-actinin-1 antibody. Co-IP was seen in the absence and, to a lesser extent, presence of BAPTA (5mM) to chelate Ca2+. In contrast, α-actinin-1 did not co-precipitate with anti-HA antibody, as a negative control. Input, 6% of total lysate. (E) Direct binding of recombinant GST-tagged α-actinin-1 with the MBP-tagged SK2 C-terminus (SK2-C). There are no non-specific interactions between SK2 or α-actinin-1 with only GST or MBP, respectively (lanes 2,3). IB; GST antibody. Inputs, 0.5% of total peptide used in IP (lane 4, α-actinin-1-GST; lane 5, GST alone). There is a lower band in lane 4 that is likely a degradation product that does not bind to SK2. (A–E) n = 3 separate experiments.
	Figure 2. α-actinin-1 and α9/10-nAChRs interact with SK2 channels in Xenopus oocytes. Immunoblots show co-precipitation of exogenous SK2 with co-expressed α-actinin-1 (A) and HA-tagged α9/10-nAChRs (B) in Xenopus laevis oocytes. As negative controls, α-actinin-1 and nAChRs did not co-precipitate with an unrelated antibody of the same IgG subclass (anti-mGluR5; ctl lane in A and B) and SK2 did not co-precipitate with endogenous Na+/K+ ATPase (B, lower panel). Input, 6% of total membrane fraction (M) and lysate (tot) for all panels. n = 4 separate experiments.
	Figure 5. ARK alternative splicing alters interactions of SK2 with α9/10-nAChRs and α-actinin-1. Co-immunoprecipitation of α -actinin-1 (A; see also Fig. 2A) and HA-tagged α9/10-nAChRs (C) with SK2 and SK2-ARK exogenously expressed in Xenopus oocytes. (A and C) Negative controls show no α-actinin-1 or α9/10-nAChR co-precipitation with an unrelated antibody (ctl lanes) or (C) with SK2 antibody from oocytes not transfected with exogeneous SK2. Input in (A and C), 6% of total membrane fraction (M) and lysate (tot). (B) Direct interactions of GST-tagged α -actinin-1 with MBP-tagged SK2 or SK2-ARK C-termini. IP: MBP antibody to pull down SK2, IB: GST antibody. Negative controls show little or no nonspecific interactions with MBP or GST alone (lanes 2,4,5). Input, 0.5% of GST-α-actinin-1 and GST used in pulldown. The lower band in lane 6 is likely a degradation product. (A–C) Graphs show normalized band densities of co-precipitated proteins relative to precipitated SK2 or MBP-tagged SK2 or SK2-ARK peptide in each lane. In each experiment, normalized protein levels co-precipitated with SK2-ARK were calculated as a percentage of co-precipitation with SK2 (100%). Bars represent mean percentage ± SEM * 95% confidence interval was 103.83–241.27% of SK2 values. ** 99.99% confidence interval was 70.00–92.50% of SK2 values. n = 4 separate experiments (A) and 3 separate experiments (B and C).
	Figure 3. Increases in developmental expression of SK2-ARK splice variant in chicken cochlear hair cells in vivo. (A) Sequence alignments of the C-terminus of chicken (ch) splice variants, SK2 and SK2-ARK (24), mouse SK2 (GenBank accession number P58390) and SK2-ARK, trout SK2 (NP_001117783) and mouse SK1 (Q9EQR3). Numbers indicate amino acids of chicken SK2. Source: http://multalin.toulouse.inra.fr/multalin/. (B) ARK insertion (lower sequence) creates a unique restriction endonuclease site (Hpy188I) that is not present in chicken SK2 (upper sequence) that lacks the insert. (C) Quantification of relative abundance of SK2-ARK mRNA, compared with SK2, during chicken cochlear development, ranging from embryonic day (E)12–14 to E20. Identification of cDNA clones of SK2-ARK (lanes 1,3) and SK2 (lanes 2,4) by using Hpy188I restriction digestion and size separation of the products by agarose gel electrophoresis. The cDNAs were generated by RT-PCR amplification from cochleae total RNA with primers to conserved sequences that flank the ARK insertion site and subcloning (~150 clones analyzed in total per age). Bottom: quantification of the relative abundance of SK2-ARK transcript. n = 3 separate RT-PCR experiments with independent RNA extractions, 50–60 clones per age per experiment. (D) Graph of developmental increases in the relative abundance of SK2-ARK transcripts, detected by q-PCR, in the mammalian hippocampus (HC) and cortex (Ctx) from postnatal day 8 to 3 mo of age (adult). n = 6 animals per age, 3 separate q-PCR experiments with independent RNA extractions. Bars and data points in (C and D) represent mean ± SEM; * P < 0.01 Student t test compared with levels at E12–14.
	Figure 4. Ca2+ gating of SK2 and SK2-ARK channels. (A) Mean normalized Ca2+ response curves for SK2 (solid line) and SK2-ARK (dashed line) currents recorded in inside-out patches of Xenopus oocyte membranes. SK2 and SK2-ARK currents during 50mV voltage steps were recorded in different Ca2+ concentrations. Normalized curves were fitted with the Hill equation. * P < 5 x 10−7, Student t test; n = 13 for both SK2 and SK2-ARK. (B) Recombinant peptide binding assay shows direct binding of CaM to MBP-tagged SK2 and SK2-ARK C-termini in the presence of 5mM BAPTA or 1mM CaCl2. Input, 1% of CaM used in pulldown. Histograms show band densities of co-precipitated CaM normalized to SK2-C-MBP or SK2-ARK-C-MBP in each lane (detected with anti-MBP antibody). In each experiment, normalized levels of CaM co-precipitated with SK2-ARK-MBP were calculated as a percentage of CaM co-precipitation with SK2-MBP (100%). Bars represent mean percentage ± SEM ** 95% confidence interval was 103.73–179.95% of SK2 values. n = 3 separate experiments.
	Figure 6. Surface membrane levels of SK2, SK2-ARK, and α9/10-nAChRs. (A) Histogram of SK2 and SK2-ARK surface levels, normalized biotinylated band densities at time 0 (precipitation immediately following biotinylation). (B) Histogram of α9/10-nAChRs surface levels expressed alone, or co-expressed with SK2, or SK2-ARK, all with α-actinin-1, normalized band densities at time 0. (C) Graph of the remaining surface levels of biotinylated SK2 or SK2-ARK at indicated time points relative to levels at time 0, indicating their relative stability in the surface membrane. Graphs indicate band densities of precipitated SK2 or nAChRs normalized to input membrane expression. In each experiment, normalized levels of biotinylated SK2-ARK (A) or nAChRs co-expressed with SK2-ARK or no SK2 (B) were calculated as a percentage of biotinylated SK2 or nAChRs co-expressed with SK2 (100%). In each experiment (C), remaining levels of biotinylated SK2 or SK2-ARK were calculated as a percentage of biotinylated levels at time 0. Bars represent mean ± SEM * 99.5% confidence interval was 9.64–93.78% of co-expression with SK2. ** 99.99% confidence interval was -4.14–78.45% of co-expression with SK2. *** 99.99% confidence interval was -2.47–61.41% of SK2 values. n = 5 separate experiments (A) and 3–4 separate experiments (B and C).
	Figure 7. Ca2+ and CaM modulate interactions of SK2 and SK2-ARK with α-actinin-1. (A) Recombinant peptide binding assays showing effects of Ca2+ and CaM on binding of α-actinin-1 to SK2 and SK2-ARK. Purified recombinant CaM at the indicated concentrations was incubated with equal amounts of MBP-tagged SK2 or SK2-ARK C-terminus constructs and amylose beads in buffer containing 5mM BAPTA or 1mM CaCl2 prior to incubation with GST-tagged α-actinin-1. Immunoblots and graph (lower left) show that elevated Ca2+ (buffer containing 1mM CaCl2) increases the levels of GST-tagged α-actinin-1 bound to SK2 and SK2-ARK C-terminal peptides, compared with low Ca2+ (buffer containing 5mM BAPTA). Immunoblots and graph (lower right) show that CaM, in the presence of Ca2+, decreases the amount of α-actinin-1 bound to both isoformsbut only to SK2-ARK in the absence of Ca2+ (B) Immunoblots and graph show decreased co-precipitation of exogenous α-actinin-1 with SK2 and SK2-ARK from oocytes incubated with BAPTA-AM (10mM) to chelate intracellular Ca2+ prior to and during lysis. All graphs show normalized band densities of bound α-actinin-1-GST (A) or α-actinin-1 (B) normalized to MBP-tagged SK2 construct or SK2 in each lane. In each experiment, normalized protein levels co-precipitated with SK2-ARK were calculated as a percentage of co-precipitation with SK2 (100%). Bars represent mean ± SEM * 95% confidence interval was 59.15–98.29% of SK2 values with BAPTA. ** P < 0.0005 Students t test; † 99.99% confidence interval was 234.91–400.48% of SK2 values with BAPTA. *** 99.99% confidence interval was 55.21–90.01% of SK2-ARK values with 10 μM CaM; † 99.99% confidence intervals were 5.27–59.20% of SK2 values and 11.43–52.56% of SK2-ARK values with 10 μM CaM. n = 3 separate experiments (A and B).
	Figure 8. Ca2+ differentially modulates interactions of SK2 and SK2-ARK with α9/10-nAChRs. Immunoblots show that incubation with BAPTA-AM (10mM) to chelate intracellular Ca2+ leads to increased co-precipitation of HA-tagged α9/10-nAChRs with SK2, but not with SK2-ARK, from oocytes. Graph shows normalized band densities of co-precipitated α9/10-nAChRs relative to precipitated SK2 in each lane. In each experiment, normalized nAChR levels co-precipitated with SK2-ARK were calculated as a percentage of co-precipitation with SK2 (100%). Bars represent mean ± SEM * 99.99% confidence interval was 109.34–290.84% of control SK2 values. n = 4 separate experiments.
	Figure 9. Summary model of the effects of SK2 alternative splicing and Ca2+ signaling on the α9/10-nAChR-SK2 channel postsynaptic complex. The model indicates that SK2 channels and α9/10-nAChRs physically interact within a multi-molecular complex that includes the actin-binding protein α-actinin-1 and that Ca2+ modulates the interactions. SK2-ARK, compared with SK2, channels exhibit reduced binding to α-actinin-1, and increased association with α9/10-nAChRs. However, SK2-ARK surface membrane levels are lower than those of SK2. Interactions between α-actinin-1 and SK2 (A) and SK2-ARK (B) are similarly modulated by Ca2+ (enhanced, arrow) and Ca2+-CaM (reduced). Ca2+ decreases SK2 interactions with α9/10-nAChRs, possibly serving as a mechanism to regulate efferent inhibition. In comparison, Ca2+ does not alter or modestly enhances the SK2-ARK::α9/10-nAChR interactions (dotted arrow), suggesting that they are less prone to inhibition by Ca2+. Additional differences, such as Ca2+ sensitivity (see text), suggest that developmental increases in SK2-ARK relative levels may modulate synaptic activity in cochlear hair cells and neurons.
	Figure 1. α-actinin localizes to olivocochlear postsynaptic sites in sensory hair cells and interacts with SK2 channels. (A–C) Micrographs of fluorescent immunolabeling of E19 chicken hair cells show that SK2 (red, A) and the postsynaptic scaffold protein S-SCAM (red, B) are predominantly concentrated at olivocochlear postsynaptic sites, based on juxtaposition and partial overlap (yellow) with SV2 labeled presynaptic terminal vesicle clusters (green, A and B). α-actinin (red, C) is also enriched at postsynaptic sites, based on co-localization and strong overlap with S-SCAM (green, C). Lower panels: Profiles of pixel intensity peaks show partial overlap of SK2 with SV2 (A) and S-SCAM with SV2 (B), and almost complete overlap of α-actinin with S-SCAM (C). Pixel intensities were measured along a line drawn vertically across the postsynaptic and presynaptic membranes (white lines shown in middle panels). Scale bar = 5μM. (D) Co-precipitation of SK2 channels with α-actinin-1 from E20 chicken cochlea lysates, detected by immunoprecipitating (IP) SK2 and immunoblotting (IB) with an anti-α-actinin-1 antibody. Co-IP was seen in the absence and, to a lesser extent, presence of BAPTA (5mM) to chelate Ca2+. In contrast, α-actinin-1 did not co-precipitate with anti-HA antibody, as a negative control. Input, 6% of total lysate. (E) Direct binding of recombinant GST-tagged α-actinin-1 with the MBP-tagged SK2 C-terminus (SK2-C). There are no non-specific interactions between SK2 or α-actinin-1 with only GST or MBP, respectively (lanes 2,3). IB; GST antibody. Inputs, 0.5% of total peptide used in IP (lane 4, α-actinin-1-GST; lane 5, GST alone). There is a lower band in lane 4 that is likely a degradation product that does not bind to SK2. (A–E) n = 3 separate experiments.
	Figure 2. α-actinin-1 and α9/10-nAChRs interact with SK2 channels in Xenopus oocytes. Immunoblots show co-precipitation of exogenous SK2 with co-expressed α-actinin-1 (A) and HA-tagged α9/10-nAChRs (B) in Xenopus laevis oocytes. As negative controls, α-actinin-1 and nAChRs did not co-precipitate with an unrelated antibody of the same IgG subclass (anti-mGluR5; ctl lane in A and B) and SK2 did not co-precipitate with endogenous Na+/K+ ATPase (B, lower panel). Input, 6% of total membrane fraction (M) and lysate (tot) for all panels. n = 4 separate experiments.
	Figure 5. ARK alternative splicing alters interactions of SK2 with α9/10-nAChRs and α-actinin-1. Co-immunoprecipitation of α -actinin-1 (A; see also Fig. 2A) and HA-tagged α9/10-nAChRs (C) with SK2 and SK2-ARK exogenously expressed in Xenopus oocytes. (A and C) Negative controls show no α-actinin-1 or α9/10-nAChR co-precipitation with an unrelated antibody (ctl lanes) or (C) with SK2 antibody from oocytes not transfected with exogeneous SK2. Input in (A and C), 6% of total membrane fraction (M) and lysate (tot). (B) Direct interactions of GST-tagged α -actinin-1 with MBP-tagged SK2 or SK2-ARK C-termini. IP: MBP antibody to pull down SK2, IB: GST antibody. Negative controls show little or no nonspecific interactions with MBP or GST alone (lanes 2,4,5). Input, 0.5% of GST-α-actinin-1 and GST used in pulldown. The lower band in lane 6 is likely a degradation product. (A–C) Graphs show normalized band densities of co-precipitated proteins relative to precipitated SK2 or MBP-tagged SK2 or SK2-ARK peptide in each lane. In each experiment, normalized protein levels co-precipitated with SK2-ARK were calculated as a percentage of co-precipitation with SK2 (100%). Bars represent mean percentage ± SEM * 95% confidence interval was 103.83–241.27% of SK2 values. ** 99.99% confidence interval was 70.00–92.50% of SK2 values. n = 4 separate experiments (A) and 3 separate experiments (B and C).
	Figure 3. Increases in developmental expression of SK2-ARK splice variant in chicken cochlear hair cells in vivo. (A) Sequence alignments of the C-terminus of chicken (ch) splice variants, SK2 and SK2-ARK (24), mouse SK2 (GenBank accession number P58390) and SK2-ARK, trout SK2 (NP_001117783) and mouse SK1 (Q9EQR3). Numbers indicate amino acids of chicken SK2. Source: http://multalin.toulouse.inra.fr/multalin/. (B) ARK insertion (lower sequence) creates a unique restriction endonuclease site (Hpy188I) that is not present in chicken SK2 (upper sequence) that lacks the insert. (C) Quantification of relative abundance of SK2-ARK mRNA, compared with SK2, during chicken cochlear development, ranging from embryonic day (E)12–14 to E20. Identification of cDNA clones of SK2-ARK (lanes 1,3) and SK2 (lanes 2,4) by using Hpy188I restriction digestion and size separation of the products by agarose gel electrophoresis. The cDNAs were generated by RT-PCR amplification from cochleae total RNA with primers to conserved sequences that flank the ARK insertion site and subcloning (~150 clones analyzed in total per age). Bottom: quantification of the relative abundance of SK2-ARK transcript. n = 3 separate RT-PCR experiments with independent RNA extractions, 50–60 clones per age per experiment. (D) Graph of developmental increases in the relative abundance of SK2-ARK transcripts, detected by q-PCR, in the mammalian hippocampus (HC) and cortex (Ctx) from postnatal day 8 to 3 mo of age (adult). n = 6 animals per age, 3 separate q-PCR experiments with independent RNA extractions. Bars and data points in (C and D) represent mean ± SEM; * P < 0.01 Student t test compared with levels at E12–14.
	Figure 6. Surface membrane levels of SK2, SK2-ARK, and α9/10-nAChRs. (A) Histogram of SK2 and SK2-ARK surface levels, normalized biotinylated band densities at time 0 (precipitation immediately following biotinylation). (B) Histogram of α9/10-nAChRs surface levels expressed alone, or co-expressed with SK2, or SK2-ARK, all with α-actinin-1, normalized band densities at time 0. (C) Graph of the remaining surface levels of biotinylated SK2 or SK2-ARK at indicated time points relative to levels at time 0, indicating their relative stability in the surface membrane. Graphs indicate band densities of precipitated SK2 or nAChRs normalized to input membrane expression. In each experiment, normalized levels of biotinylated SK2-ARK (A) or nAChRs co-expressed with SK2-ARK or no SK2 (B) were calculated as a percentage of biotinylated SK2 or nAChRs co-expressed with SK2 (100%). In each experiment (C), remaining levels of biotinylated SK2 or SK2-ARK were calculated as a percentage of biotinylated levels at time 0. Bars represent mean ± SEM * 99.5% confidence interval was 9.64–93.78% of co-expression with SK2. ** 99.99% confidence interval was -4.14–78.45% of co-expression with SK2. *** 99.99% confidence interval was -2.47–61.41% of SK2 values. n = 5 separate experiments (A) and 3–4 separate experiments (B and C).

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