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      Kv7 Channels Can Function without Constitutive Calmodulin Tethering

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          Abstract

          M-channels are voltage-gated potassium channels composed of Kv7.2-7.5 subunits that serve as important regulators of neuronal excitability. Calmodulin binding is required for Kv7 channel function and mutations in Kv7.2 that disrupt calmodulin binding cause Benign Familial Neonatal Convulsions (BFNC), a dominantly inherited human epilepsy. On the basis that Kv7.2 mutants deficient in calmodulin binding are not functional, calmodulin has been defined as an auxiliary subunit of Kv7 channels. However, we have identified a presumably phosphomimetic mutation S511D that permits calmodulin-independent function. Thus, our data reveal that constitutive tethering of calmodulin is not required for Kv7 channel function.

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          Calmodulin is essential for cardiac IKS channel gating and assembly: impaired function in long-QT mutations.

          Nicole Schmitt, L. Shamgar, Bernard Attali … (2006)
          The slow IKS K+ channel plays a major role in repolarizing the cardiac action potential and consists of the assembly of KCNQ1 and KCNE1 subunits. Mutations in either KCNQ1 or KCNE1 genes produce the long-QT syndrome, a life-threatening ventricular arrhythmia. Here, we show that long-QT mutations located in the KCNQ1 C terminus impair calmodulin (CaM) binding, which affects both channel gating and assembly. The mutations produce a voltage-dependent macroscopic inactivation and dramatically alter channel assembly. KCNE1 forms a ternary complex with wild-type KCNQ1 and Ca(2+)-CaM that prevents inactivation, facilitates channel assembly, and mediates a Ca(2+)-sensitive increase of IKS-current, with a considerable Ca(2+)-dependent left-shift of the voltage-dependence of activation. Coexpression of KCNQ1 or IKS channels with a Ca(2+)-insensitive CaM mutant markedly suppresses the currents and produces a right shift in the voltage-dependence of channel activation. KCNE1 association to KCNQ1 long-QT mutants significantly improves mutant channel expression and prevents macroscopic inactivation. However, the marked right shift in channel activation and the subsequent decrease in current amplitude cannot restore normal levels of IKS channel activity. Our data indicate that in healthy individuals, CaM binding to KCNQ1 is essential for correct channel folding and assembly and for conferring Ca(2+)-sensitive IKS-current stimulation, which increases the cardiac repolarization reserve and hence prevents the risk of ventricular arrhythmias.
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            Calmodulin Mediates Ca2+-dependent Modulation of M-type K+ Channels

            Nikita Gamper, Mark Shapiro (2003)
            To quantify the modulation of KCNQ2/3 current by [Ca2+]i and to test if calmodulin (CaM) mediates this action, simultaneous whole-cell recording and Ca2+ imaging was performed on CHO cells expressing KCNQ2/3 channels, either alone, or together with wild-type (wt) CaM, or dominant-negative (DN) CaM. We varied [Ca2+]i from 400 nM with ionomycin (5 μM) added to either a 2 mM Ca2+, or EGTA-buffered Ca2+-free, solution. Coexpression of wt CaM made KCNQ2/3 currents highly sensitive to [Ca2+]i (IC50 70 ± 20 nM, max inhibition 73%, n = 10). However, coexpression of DN CaM rendered KCNQ2/3 currents largely [Ca2+]i insensitive (max inhibition 8 ± 3%, n = 10). In cells without cotransfected CaM, the Ca2+ sensitivity was variable but generally weak. [Ca2+]i modulation of M current in superior cervical ganglion (SCG) neurons followed the same pattern as in CHO cells expressed with KCNQ2/3 and wt CaM, suggesting that endogenous M current is also highly sensitive to [Ca2+]i. Coimmunoprecipitations showed binding of CaM to KCNQ2–5 that was similar in the presence of 5 mM Ca2+ or 5 mM EGTA. Gel-shift analyses suggested Ca2+-dependent CaM binding to an “IQ-like” motif present in the carboxy terminus of KCNQ2–5. We tested whether bradykinin modulation of M current in SCG neurons uses CaM. Wt or DN CaM was exogenously expressed in SCG cells using pseudovirions or the biolistic “gene gun.” Using both methods, expression of both wt CaM and DN CaM strongly reduced bradykinin inhibition of M current, but for all groups muscarinic inhibition was unaffected. Cells expressed with wt CaM had strongly reduced tonic current amplitudes as well. We observed similar [Ca2+]i rises by bradykinin in all the groups of cells, indicating that CaM did not affect Ca2+ release from stores. We conclude that M-type currents are highly sensitive to [Ca2+]i and that calmodulin acts as their Ca2+ sensor.
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              Calmodulin as an ion channel subunit.

              Yoshiro Saimi, Ching Kung (2001)
              A surprising variety of ion channels found in a wide range of species from Homo to Paramecium use calmodulin (CaM) as their constitutive or dissociable Ca(2+)-sensing subunits. The list includes voltage-gated Ca(2+) channels, various Ca(2+)- or ligand-gated channels, Trp family channels, and even the Ca(2+)-induced Ca(2+) release channels from organelles. Our understanding of CaM chemistry and its relation to enzymes has been instructive in channel research, yet the intense study of CaM regulation of ion channels has also revealed unexpected CaM chemistry. The findings on CaM channel interactions have indicated the existence of secondary interaction sites in addition to the primary CaM-binding peptides and the functional differences between the N- and C-lobes of CaM. The study of CaM in channel biology will figure into our understanding on how this uniform, universal, vital, and ubiquitous Ca(2+) decoder coordinates the myriad local and global cell physiological transients.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2011
                Publication date (Electronic): 28 September 2011
                Volume: 6
                Issue: 9
                Electronic Location Identifier: e25508
                Affiliations
                [1 ]Unidad de Biofísica, Consejo Superior de Investigaciones Científicas-Universidad del País Vasco/Euskal Herriko Unibersitatea, Leioa, Spain
                [2 ]Dept. Farmacología, Universidad del País Vasco, Leioa, Spain
                [3 ]Dept. Fisiología, Universidad del País Vasco, Leioa, Spain
                Sackler Medical School-Tel Aviv University, Israel
                Author notes

                Conceived and designed the experiments: AV JCG-P P. Aivar A. Alaimo. Performed the experiments: JCG-P P. Aivar A. Alaimo A. Alberti AE JF-O OC TZ. Analyzed the data: JCG-P A. Alaimo A. Alberti TZ. Contributed reagents/materials/analysis tools: PV P. Areso. Wrote the paper: AV. Reviewed the design of experiments: PV. Assisted in the execution of imaging experiments: MR. Conceived experiments: P. Areso.

                [¤a]

                Current address: Current address: Max Planck Institute for Experimental Medicine, Göttingen, Germany

                [¤b]

                Current address: Instituto Cajal, Av. Dr. Arce 37, Madrid, Spain

                [¤c]

                Current address: Department of Neurology, University of California San Francisco, Genentech Hall, San Francisco, California, USA

                [¤d]

                Current address: Innoprot, Parque Tecnológico de Bizkaia, Derio, Spain

                Article
                Publisher ID: PONE-D-11-09476
                DOI: 10.1371/journal.pone.0025508
                PMC ID: 3182250
                PubMed ID: 21980481
                SO-VID: 7af75f87-de6e-465a-8c1a-d33d735de77c
                Copyright © Gomez-Posada et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 25 May 2011
                Date accepted : 5 September 2011
                Page count
                Pages: 9
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Genetics
                Subject: Human Genetics
                Subject: Molecular Cell Biology
                Subject: Signal Transduction
                Subject: Signaling in Cellular Processes
                Subject: Neuroscience
                Subject: Cellular Neuroscience
                Subject: Ion Channels
                Subject: Medicine
                Subject: Neurology
                Subject: Epilepsy

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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