{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T18:36:46Z","timestamp":1774463806941,"version":"3.50.1"},"reference-count":76,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T00:00:00Z","timestamp":1668124800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T00:00:00Z","timestamp":1668124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Mol Neurobiol"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Acetylcholine can excite neurons by suppressing M-type (KCNQ) potassium channels. This effect is mediated by M<jats:sub>1<\/jats:sub>muscarinic receptors coupled to the G<jats:sub>q<\/jats:sub>protein. Although PIP<jats:sub>2<\/jats:sub>depletion and PKC activation have been strongly suggested to contribute to muscarinic inhibition of M currents (I<jats:sub>M<\/jats:sub>), direct evidence is lacking. We investigated the mechanism involved in muscarinic inhibition of I<jats:sub>M<\/jats:sub>with Ca<jats:sup>2+<\/jats:sup>measurement and electrophysiological studies in both neuronal (rat sympathetic neurons) and heterologous (HEK cells expressing KCNQ2\/KCNQ3) preparations. We found that muscarinic inhibition of I<jats:sub>M<\/jats:sub>was not blocked either by PIP<jats:sub>2<\/jats:sub>or by calphostin C, a PKC inhibitor. We then examined whether muscarinic inhibition of I<jats:sub>M<\/jats:sub>uses multiple signaling pathways by blocking both PIP<jats:sub>2<\/jats:sub>depletion and PKC activation. This maneuver, however, did not block muscarinic inhibition of I<jats:sub>M<\/jats:sub>. Additionally, muscarinic inhibition of I<jats:sub>M<\/jats:sub>was not prevented either by sequestering of G-protein \u03b2\u03b3 subunits from G<jats:sub>\u03b1<\/jats:sub>-transducin or anti-G<jats:sub>\u03b2\u03b3<\/jats:sub>antibody or by preventing intracellular trafficking of channel proteins with blebbistatin, a class-II myosin inhibitor. Finally, we re-examined the role of Ca<jats:sup>2+<\/jats:sup>signals in muscarinic inhibition of I<jats:sub>M<\/jats:sub>. Ca<jats:sup>2+<\/jats:sup>measurements showed that muscarinic stimulation increased intracellular Ca<jats:sup>2+<\/jats:sup>and was comparable to the Ca<jats:sup>2+<\/jats:sup>mobilizing effect of bradykinin. Accordingly, 20-mM of BAPTA significantly suppressed muscarinic inhibition of I<jats:sub>M<\/jats:sub>. In contrast, muscarinic inhibition of I<jats:sub>M<\/jats:sub>was completely insensitive to 20-mM EGTA. Taken together, these data suggest a role of Ca<jats:sup>2+<\/jats:sup>signaling in muscarinic modulation of I<jats:sub>M<\/jats:sub>. The differential effects of EGTA and BAPTA imply that Ca<jats:sup>2+<\/jats:sup>microdomains or spatially local Ca<jats:sup>2+<\/jats:sup>signals contribute to inhibition of I<jats:sub>M<\/jats:sub>.<\/jats:p>","DOI":"10.1007\/s10571-022-01303-7","type":"journal-article","created":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T17:04:51Z","timestamp":1668186291000},"page":"2257-2271","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Involvement of Ca2+ in Signaling Mechanisms Mediating Muscarinic Inhibition of M Currents in Sympathetic Neurons"],"prefix":"10.1007","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5707-3636","authenticated-orcid":false,"given":"Jin-Young","family":"Yoon","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Won-Kyung","family":"Ho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,11,11]]},"reference":[{"key":"1303_CR1","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/s1054-3589(08)60281-1","volume":"35","author":"SP Aiken","year":"1996","unstructured":"Aiken SP, Zaczek R, Brown BS (1996) Pharmacology of the neurotransmitter release enhancer linopirdine (DuP 996), and insights into its mechanism of action. Adv Pharmacol 35:349\u2013384. https:\/\/doi.org\/10.1016\/s1054-3589(08)60281-1","journal-title":"Adv Pharmacol"},{"issue":"5089","key":"1303_CR2","doi-asserted-by":"publisher","first-page":"1812","DOI":"10.1126\/science.1465619","volume":"258","author":"NL Allbritton","year":"1992","unstructured":"Allbritton NL, Meyer T, Stryer L (1992) Range of messenger action of calcium ion and inositol 1,4,5-trisphosphate. Science 258(5089):1812\u20131815. https:\/\/doi.org\/10.1126\/science.1465619","journal-title":"Science"},{"issue":"2","key":"1303_CR3","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1073\/pnas.88.2.652","volume":"88","author":"DJ Beech","year":"1991","unstructured":"Beech DJ, Bernheim L, Mathie A, Hille B (1991) Intracellular Ca2+ buffers disrupt muscarinic suppression of Ca2+ current and M current in rat sympathetic neurons. Proc Natl Acad Sci USA 88(2):652\u2013656. https:\/\/doi.org\/10.1073\/pnas.88.2.652","journal-title":"Proc Natl Acad Sci USA"},{"issue":"6","key":"1303_CR4","first-page":"1165","volume":"57","author":"E Bofill-Cardona","year":"2000","unstructured":"Bofill-Cardona E, Vartian N, Nanoff C, Freissmuth M, Boehm S (2000) Two different signaling mechanisms involved in the excitation of rat sympathetic neurons by uridine nucleotides. Mol Pharmacol 57(6):1165\u20131172","journal-title":"Mol Pharmacol"},{"issue":"8","key":"1303_CR5","doi-asserted-by":"publisher","first-page":"2943","DOI":"10.1073\/pnas.86.8.2943","volume":"86","author":"MM Bosma","year":"1989","unstructured":"Bosma MM, Hille B (1989) Protein kinase C is not necessary for peptide-induced suppression of M current or for desensitization of the peptide receptors. Proc Natl Acad Sci USA 86(8):2943\u20132947. https:\/\/doi.org\/10.1073\/pnas.86.8.2943","journal-title":"Proc Natl Acad Sci USA"},{"issue":"5748","key":"1303_CR6","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1038\/283673a0","volume":"283","author":"DA Brown","year":"1980","unstructured":"Brown DA, Adams PR (1980) Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone. Nature 283(5748):673\u2013676. https:\/\/doi.org\/10.1038\/283673a0","journal-title":"Nature"},{"issue":"2\u20134","key":"1303_CR7","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/s0079-6107(00)00004-3","volume":"73","author":"BS Brown","year":"2000","unstructured":"Brown BS, Yu SP (2000) Modulation and genetic identification of the M channel. Prog Biophys Mol Biol 73(2\u20134):135\u2013166. https:\/\/doi.org\/10.1016\/s0079-6107(00)00004-3","journal-title":"Prog Biophys Mol Biol"},{"issue":"3","key":"1303_CR8","doi-asserted-by":"publisher","first-page":"C543","DOI":"10.1152\/ajpcell.00025.2005","volume":"289","author":"SG Brown","year":"2005","unstructured":"Brown SG, Thomas A, Dekker LV, Tinker A, Leaney JL (2005) PKC-delta sensitizes Kir3.1\/3.2 channels to changes in membrane phospholipid levels after M3 receptor activation in HEK-293 cells. Am J Physiol Cell Physiol 289(3):C543-556. https:\/\/doi.org\/10.1152\/ajpcell.00025.2005","journal-title":"Am J Physiol Cell Physiol"},{"issue":"Pt 1","key":"1303_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1042\/bj3530001","volume":"353","author":"RD Burgoyne","year":"2001","unstructured":"Burgoyne RD, Weiss JL (2001) The neuronal calcium sensor family of Ca2+-binding proteins. Biochem J 353(Pt 1):1\u201312","journal-title":"Biochem J"},{"issue":"Pt 3","key":"1303_CR10","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1113\/jphysiol.1994.sp020203","volume":"477","author":"MP Caulfield","year":"1994","unstructured":"Caulfield MP, Jones S, Vallis Y, Buckley NJ, Kim GD, Milligan G, Brown DA (1994) Muscarinic M-current inhibition via G alpha q\/11 and alpha-adrenoceptor inhibition of Ca2+ current via G alpha o in rat sympathetic neurones. J Physiol 477(Pt 3):415\u2013422. https:\/\/doi.org\/10.1113\/jphysiol.1994.sp020203","journal-title":"J Physiol"},{"issue":"1","key":"1303_CR11","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1074\/jbc.M004826200","volume":"276","author":"H Cho","year":"2001","unstructured":"Cho H, Nam GB, Lee SH, Earm YE, Ho WK (2001) Phosphatidylinositol 4,5-bisphosphate is acting as a signal molecule in alpha(1)-adrenergic pathway via the modulation of acetylcholine-activated K(+) channels in mouse atrial myocytes. J Biol Chem 276(1):159\u2013164. https:\/\/doi.org\/10.1074\/jbc.M004826200","journal-title":"J Biol Chem"},{"issue":"12","key":"1303_CR12","doi-asserted-by":"publisher","first-page":"4643","DOI":"10.1073\/pnas.0408844102","volume":"102","author":"H Cho","year":"2005","unstructured":"Cho H, Lee D, Lee SH, Ho WK (2005) Receptor-induced depletion of phosphatidylinositol 4,5-bisphosphate inhibits inwardly rectifying K+ channels in a receptor-specific manner. Proc Natl Acad Sci USA 102(12):4643\u20134648. https:\/\/doi.org\/10.1073\/pnas.0408844102","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"1303_CR13","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S1016-8478(23)17396-1","volume":"22","author":"H Cho","year":"2006","unstructured":"Cho H, Kim YA, Ho WK (2006) Phosphate number and acyl chain length determine the subcellular location and lateral mobility of phosphoinositides. Mol Cells 22(1):97\u2013103","journal-title":"Mol Cells"},{"issue":"50","key":"1303_CR14","doi-asserted-by":"publisher","first-page":"19411","DOI":"10.1074\/jbc.RA118.005401","volume":"293","author":"FS Choveau","year":"2018","unstructured":"Choveau FS, De la Rosa V, Bierbower SM, Hernandez CC, Shapiro MS (2018) Phosphatidylinositol 4,5-bisphosphate (PIP2) regulates KCNQ3 K(+) channels by interacting with four cytoplasmic channel domains. J Biol Chem 293(50):19411\u201319428. https:\/\/doi.org\/10.1074\/jbc.RA118.005401","journal-title":"J Biol Chem"},{"issue":"2","key":"1303_CR15","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1073\/pnas.0811615106","volume":"106","author":"HJ Chung","year":"2009","unstructured":"Chung HJ, Qian X, Ehlers M, Jan YN, Jan LY (2009) Neuronal activity regulates phosphorylation-dependent surface delivery of G protein-activated inwardly rectifying potassium channels. Proc Natl Acad Sci USA 106(2):629\u2013634. https:\/\/doi.org\/10.1073\/pnas.0811615106","journal-title":"Proc Natl Acad Sci USA"},{"issue":"3","key":"1303_CR16","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/0304-3940(81)90173-7","volume":"24","author":"A Constanti","year":"1981","unstructured":"Constanti A, Brown DA (1981) M-Currents in voltage-clamped mammalian sympathetic neurones. Neurosci Lett 24(3):289\u2013294. https:\/\/doi.org\/10.1016\/0304-3940(81)90173-7","journal-title":"Neurosci Lett"},{"issue":"4","key":"1303_CR17","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1001\/archneur.60.4.496","volume":"60","author":"EC Cooper","year":"2003","unstructured":"Cooper EC, Jan LY (2003) M-channels: neurological diseases, neuromodulation, and drug development. Arch Neurol 60(4):496\u2013500. https:\/\/doi.org\/10.1001\/archneur.60.4.496","journal-title":"Arch Neurol"},{"issue":"12","key":"1303_CR18","doi-asserted-by":"publisher","first-page":"7151","DOI":"10.1073\/pnas.95.12.7151","volume":"95","author":"H Cruzblanca","year":"1998","unstructured":"Cruzblanca H, Koh DS, Hille B (1998) Bradykinin inhibits M current via phospholipase C and Ca2+ release from IP3-sensitive Ca2+ stores in rat sympathetic neurons. Proc Natl Acad Sci USA 95(12):7151\u20137156. https:\/\/doi.org\/10.1073\/pnas.95.12.7151","journal-title":"Proc Natl Acad Sci USA"},{"issue":"53","key":"1303_CR19","doi-asserted-by":"publisher","first-page":"41732","DOI":"10.1074\/jbc.M110.153312","volume":"285","author":"S Cui","year":"2010","unstructured":"Cui S, Ho WK, Kim ST, Cho H (2010) Agonist-induced localization of Gq-coupled receptors and G protein-gated inwardly rectifying K+ (GIRK) channels to caveolae determines receptor specificity of phosphatidylinositol 4,5-bisphosphate signaling. J Biol Chem 285(53):41732\u201341739. https:\/\/doi.org\/10.1074\/jbc.M110.153312","journal-title":"J Biol Chem"},{"issue":"Pt 1","key":"1303_CR20","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1111\/j.1469-7793.1999.00101.x","volume":"520","author":"E del Rio","year":"1999","unstructured":"del Rio E, Bevilacqua JA, Marsh SJ, Halley P, Caulfield MP (1999) Muscarinic M1 receptors activate phosphoinositide turnover and Ca2+ mobilisation in rat sympathetic neurones, but this signalling pathway does not mediate M-current inhibition. J Physiol 520(Pt 1):101\u2013111. https:\/\/doi.org\/10.1111\/j.1469-7793.1999.00101.x","journal-title":"J Physiol"},{"issue":"5","key":"1303_CR21","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1016\/s0896-6273(02)01097-8","volume":"36","author":"P Delmas","year":"2002","unstructured":"Delmas P, Brown DA (2002) Junctional signaling microdomains: bridging the gap between the neuronal cell surface and Ca2+ stores. Neuron 36(5):787\u2013790. https:\/\/doi.org\/10.1016\/s0896-6273(02)01097-8","journal-title":"Neuron"},{"issue":"11","key":"1303_CR22","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1038\/nrn1785","volume":"6","author":"P Delmas","year":"2005","unstructured":"Delmas P, Brown DA (2005) Pathways modulating neural KCNQ\/M (Kv7) potassium channels. Nat Rev Neurosci 6(11):850\u2013862. https:\/\/doi.org\/10.1038\/nrn1785","journal-title":"Nat Rev Neurosci"},{"issue":"2","key":"1303_CR23","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/s0896-6273(02)00641-4","volume":"34","author":"P Delmas","year":"2002","unstructured":"Delmas P, Wanaverbecq N, Abogadie FC, Mistry M, Brown DA (2002) Signaling microdomains define the specificity of receptor-mediated InsP(3) pathways in neurons. Neuron 34(2):209\u2013220. https:\/\/doi.org\/10.1016\/s0896-6273(02)00641-4","journal-title":"Neuron"},{"issue":"7112","key":"1303_CR24","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1038\/nature05185","volume":"443","author":"G Di Paolo","year":"2006","unstructured":"Di Paolo G, De Camilli P (2006) Phosphoinositides in cell regulation and membrane dynamics. Nature 443(7112):651\u2013657. https:\/\/doi.org\/10.1038\/nature05185","journal-title":"Nature"},{"issue":"5","key":"1303_CR25","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1085\/jgp.201210886","volume":"141","author":"EJ Dickson","year":"2013","unstructured":"Dickson EJ, Falkenburger BH, Hille B (2013) Quantitative properties and receptor reserve of the IP(3) and calcium branch of G(q)-coupled receptor signaling. J Gen Physiol 141(5):521\u2013535. https:\/\/doi.org\/10.1085\/jgp.201210886","journal-title":"J Gen Physiol"},{"issue":"4","key":"1303_CR26","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1096\/fj.07-9712com","volume":"22","author":"A Etxeberria","year":"2008","unstructured":"Etxeberria A, Aivar P, Rodriguez-Alfaro JA, Alaimo A, Villace P, Gomez-Posada JC, Areso P, Villarroel A (2008) Calmodulin regulates the trafficking of KCNQ2 potassium channels. FASEB J 22(4):1135\u20131143. https:\/\/doi.org\/10.1096\/fj.07-9712com","journal-title":"FASEB J"},{"issue":"5","key":"1303_CR27","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1085\/jgp.201210887","volume":"141","author":"BH Falkenburger","year":"2013","unstructured":"Falkenburger BH, Dickson EJ, Hille B (2013) Quantitative properties and receptor reserve of the DAG and PKC branch of G(q)-coupled receptor signaling. J Gen Physiol 141(5):537\u2013555. https:\/\/doi.org\/10.1085\/jgp.201210887","journal-title":"J Gen Physiol"},{"issue":"12","key":"1303_CR28","doi-asserted-by":"publisher","first-page":"4931","DOI":"10.1523\/JNEUROSCI.23-12-04931.2003","volume":"23","author":"CP Ford","year":"2003","unstructured":"Ford CP, Stemkowski PL, Light PE, Smith PA (2003) Experiments to test the role of phosphatidylinositol 4,5-bisphosphate in neurotransmitter-induced M-channel closure in bullfrog sympathetic neurons. J Neurosci 23(12):4931\u20134941","journal-title":"J Neurosci"},{"issue":"4 Pt 1","key":"1303_CR29","doi-asserted-by":"publisher","first-page":"C829","DOI":"10.1152\/ajpcell.1995.268.4.C829","volume":"268","author":"S Foucart","year":"1995","unstructured":"Foucart S, Gibbons SJ, Brorson JR, Miller RJ (1995) Increase in [Ca2+]i by CCh in adult rat sympathetic neurons are not dependent on intracellular Ca2+ pools. Am J Physiol 268(4 Pt 1):C829-837. https:\/\/doi.org\/10.1152\/ajpcell.1995.268.4.C829","journal-title":"Am J Physiol"},{"issue":"1","key":"1303_CR30","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1085\/jgp.200208783","volume":"122","author":"N Gamper","year":"2003","unstructured":"Gamper N, Shapiro MS (2003) Calmodulin mediates Ca2+-dependent modulation of M-type K+ channels. J Gen Physiol 122(1):17\u201331. https:\/\/doi.org\/10.1085\/jgp.200208783","journal-title":"J Gen Physiol"},{"issue":"48","key":"1303_CR31","doi-asserted-by":"publisher","first-page":"10980","DOI":"10.1523\/JNEUROSCI.3869-04.2004","volume":"24","author":"N Gamper","year":"2004","unstructured":"Gamper N, Reznikov V, Yamada Y, Yang J, Shapiro MS (2004) Phosphatidylinositol [correction] 4,5-bisphosphate signals underlie receptor-specific Gq\/11-mediated modulation of N-type Ca2+ channels. J Neurosci 24(48):10980\u201310992. https:\/\/doi.org\/10.1523\/JNEUROSCI.3869-04.2004","journal-title":"J Neurosci"},{"issue":"8","key":"1303_CR32","doi-asserted-by":"publisher","first-page":"3538","DOI":"10.1091\/mbc.e04-09-0849","volume":"16","author":"N Gamper","year":"2005","unstructured":"Gamper N, Li Y, Shapiro MS (2005) Structural requirements for differential sensitivity of KCNQ K+ channels to modulation by Ca2+\/calmodulin. Mol Biol Cell 16(8):3538\u20133551. https:\/\/doi.org\/10.1091\/mbc.e04-09-0849","journal-title":"Mol Biol Cell"},{"issue":"6","key":"1303_CR33","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1016\/0092-8674(91)90547-c","volume":"65","author":"JR Geiser","year":"1991","unstructured":"Geiser JR, van Tuinen D, Brockerhoff SE, Neff MM, Davis TN (1991) Can calmodulin function without binding calcium? Cell 65(6):949\u2013959. https:\/\/doi.org\/10.1016\/0092-8674(91)90547-c","journal-title":"Cell"},{"issue":"12","key":"1303_CR34","doi-asserted-by":"publisher","first-page":"2547","DOI":"10.1113\/JP270818","volume":"593","author":"D Grundy","year":"2015","unstructured":"Grundy D (2015) Principles and standards for reporting animal experiments in the journal of physiology and experimental physiology. J Physiol 593(12):2547\u20132549. https:\/\/doi.org\/10.1113\/JP270818","journal-title":"J Physiol"},{"issue":"11","key":"1303_CR35","doi-asserted-by":"publisher","first-page":"3973","DOI":"10.1523\/JNEUROSCI.20-11-03973.2000","volume":"20","author":"JE Haley","year":"2000","unstructured":"Haley JE, Delmas P, Offermanns S, Abogadie FC, Simon MI, Buckley NJ, Brown DA (2000) Muscarinic inhibition of calcium current and M current in Galpha q-deficient mice. J Neurosci 20(11):3973\u20133979","journal-title":"J Neurosci"},{"issue":"6571","key":"1303_CR36","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1038\/380258a0","volume":"380","author":"S Herlitze","year":"1996","unstructured":"Herlitze S, Garcia DE, Mackie K, Hille B, Scheuer T, Catterall WA (1996) Modulation of Ca2+ channels by G-protein beta gamma subunits. Nature 380(6571):258\u2013262. https:\/\/doi.org\/10.1038\/380258a0","journal-title":"Nature"},{"issue":"3","key":"1303_CR37","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1085\/jgp.200810007","volume":"132","author":"CC Hernandez","year":"2008","unstructured":"Hernandez CC, Zaika O, Shapiro MS (2008a) A carboxy-terminal inter-helix linker as the site of phosphatidylinositol 4,5-bisphosphate action on Kv7 (M-type) K+ channels. J Gen Physiol 132(3):361\u2013381. https:\/\/doi.org\/10.1085\/jgp.200810007","journal-title":"J Gen Physiol"},{"issue":"7","key":"1303_CR38","doi-asserted-by":"publisher","first-page":"1811","DOI":"10.1113\/jphysiol.2007.148304","volume":"586","author":"CC Hernandez","year":"2008","unstructured":"Hernandez CC, Zaika O, Tolstykh GP, Shapiro MS (2008b) Regulation of neural KCNQ channels: signalling pathways, structural motifs and functional implications. J Physiol 586(7):1811\u20131821. https:\/\/doi.org\/10.1113\/jphysiol.2007.148304","journal-title":"J Physiol"},{"issue":"3","key":"1303_CR39","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1085\/jgp.200509309","volume":"126","author":"LF Horowitz","year":"2005","unstructured":"Horowitz LF, Hirdes W, Suh BC, Hilgemann DW, Mackie K, Hille B (2005) Phospholipase C in living cells: activation, inhibition, Ca2+ requirement, and regulation of M current. J Gen Physiol 126(3):243\u2013262. https:\/\/doi.org\/10.1085\/jgp.200509309","journal-title":"J Gen Physiol"},{"issue":"6","key":"1303_CR40","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1038\/nn1062","volume":"6","author":"N Hoshi","year":"2003","unstructured":"Hoshi N, Zhang JS, Omaki M, Takeuchi T, Yokoyama S, Wanaverbecq N, Langeberg LK, Yoneda Y, Scott JD, Brown DA, Higashida H (2003) AKAP150 signaling complex promotes suppression of the M-current by muscarinic agonists. Nat Neurosci 6(6):564\u2013571. https:\/\/doi.org\/10.1038\/nn1062","journal-title":"Nat Neurosci"},{"issue":"6571","key":"1303_CR41","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1038\/380255a0","volume":"380","author":"SR Ikeda","year":"1996","unstructured":"Ikeda SR (1996) Voltage-dependent modulation of N-type calcium channels by G-protein beta gamma subunits. Nature 380(6571):255\u2013258. https:\/\/doi.org\/10.1038\/380255a0","journal-title":"Nature"},{"issue":"Pt 3","key":"1303_CR42","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1111\/j.1469-7793.1998.747bg.x","volume":"511","author":"AJ Irving","year":"1998","unstructured":"Irving AJ, Collingridge GL (1998) A characterization of muscarinic receptor-mediated intracellular Ca2+ mobilization in cultured rat hippocampal neurones. J Physiol 511(Pt 3):747\u2013759. https:\/\/doi.org\/10.1111\/j.1469-7793.1998.747bg.x","journal-title":"J Physiol"},{"issue":"2","key":"1303_CR43","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/0896-6273(95)90295-3","volume":"14","author":"S Jones","year":"1995","unstructured":"Jones S, Brown DA, Milligan G, Willer E, Buckley NJ, Caulfield MP (1995) Bradykinin excites rat sympathetic neurons by inhibition of M current through a mechanism involving B2 receptors and G alpha q\/11. Neuron 14(2):399\u2013405. https:\/\/doi.org\/10.1016\/0896-6273(95)90295-3","journal-title":"Neuron"},{"issue":"4","key":"1303_CR44","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1016\/s0896-6273(00)80740-0","volume":"22","author":"PJ Kammermeier","year":"1999","unstructured":"Kammermeier PJ, Ikeda SR (1999) Expression of RGS2 alters the coupling of metabotropic glutamate receptor 1a to M-type K+ and N-type Ca2+ channels. Neuron 22(4):819\u2013829. https:\/\/doi.org\/10.1016\/s0896-6273(00)80740-0","journal-title":"Neuron"},{"key":"1303_CR45","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.17159","author":"HJ Kim","year":"2016","unstructured":"Kim HJ, Jeong MH, Kim KR, Jung CY, Lee SY, Kim H, Koh J, Vuong TA, Jung S, Yang H, Park SK, Choi D, Kim SH, Kang K, Sohn JW, Park JM, Jeon D, Koo SH, Ho WK, Kang JS, Kim ST, Cho H (2016) Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression. Elife. https:\/\/doi.org\/10.7554\/eLife.17159","journal-title":"Elife"},{"issue":"6","key":"1303_CR46","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1016\/0896-6273(91)90240-z","volume":"6","author":"A Kirkwood","year":"1991","unstructured":"Kirkwood A, Simmons MA, Mather RJ, Lisman J (1991) Muscarinic suppression of the M-current is mediated by a rise in internal Ca2+ concentration. Neuron 6(6):1009\u20131014. https:\/\/doi.org\/10.1016\/0896-6273(91)90240-z","journal-title":"Neuron"},{"issue":"33","key":"1303_CR47","doi-asserted-by":"publisher","first-page":"30315","DOI":"10.1074\/jbc.M201132200","volume":"277","author":"S Koizumi","year":"2002","unstructured":"Koizumi S, Rosa P, Willars GB, Challiss RA, Taverna E, Francolini M, Bootman MD, Lipp P, Inoue K, Roder J, Jeromin A (2002) Mechanisms underlying the neuronal calcium sensor-1-evoked enhancement of exocytosis in PC12 cells. J Biol Chem 277(33):30315\u201330324. https:\/\/doi.org\/10.1074\/jbc.M201132200","journal-title":"J Biol Chem"},{"issue":"12","key":"1303_CR48","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0082290","volume":"8","author":"A Kosenko","year":"2013","unstructured":"Kosenko A, Hoshi N (2013) A change in configuration of the calmodulin-KCNQ channel complex underlies Ca2+-dependent modulation of KCNQ channel activity. PLoS ONE 8(12):e82290. https:\/\/doi.org\/10.1371\/journal.pone.0082290","journal-title":"PLoS ONE"},{"issue":"14","key":"1303_CR49","doi-asserted-by":"publisher","first-page":"3147","DOI":"10.1038\/emboj.2012.156","volume":"31","author":"A Kosenko","year":"2012","unstructured":"Kosenko A, Kang S, Smith IM, Greene DL, Langeberg LK, Scott JD, Hoshi N (2012) Coordinated signal integration at the M-type potassium channel upon muscarinic stimulation. EMBO J 31(14):3147\u20133156. https:\/\/doi.org\/10.1038\/emboj.2012.156","journal-title":"EMBO J"},{"key":"1303_CR50","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.663840","volume":"12","author":"M Kruse","year":"2021","unstructured":"Kruse M, Whitten RJ (2021) Control of neuronal excitability by cell surface receptor density and phosphoinositide metabolism. Front Pharmacol 12:663840. https:\/\/doi.org\/10.3389\/fphar.2021.663840","journal-title":"Front Pharmacol"},{"issue":"14","key":"1303_CR51","doi-asserted-by":"publisher","first-page":"10939","DOI":"10.1074\/jbc.M109.048868","volume":"285","author":"SY Lee","year":"2010","unstructured":"Lee SY, Choi HK, Kim ST, Chung S, Park MK, Cho JH, Ho WK, Cho H (2010) Cholesterol inhibits M-type K+ channels via protein kinase C-dependent phosphorylation in sympathetic neurons. J Biol Chem 285(14):10939\u201310950. https:\/\/doi.org\/10.1074\/jbc.M109.048868","journal-title":"J Biol Chem"},{"issue":"43","key":"1303_CR52","doi-asserted-by":"publisher","first-page":"9825","DOI":"10.1523\/JNEUROSCI.2597-05.2005","volume":"25","author":"Y Li","year":"2005","unstructured":"Li Y, Gamper N, Hilgemann DW, Shapiro MS (2005) Regulation of Kv7 (KCNQ) K+ channel open probability by phosphatidylinositol 4,5-bisphosphate. J Neurosci 25(43):9825\u20139835. https:\/\/doi.org\/10.1523\/JNEUROSCI.2597-05.2005","journal-title":"J Neurosci"},{"key":"1303_CR53","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.neuro.2014.01.008","volume":"43","author":"M Meijer","year":"2014","unstructured":"Meijer M, Hamers T, Westerink RHS (2014) Acute disturbance of calcium homeostasis in PC12 cells as a novel mechanism of action for (sub)micromolar concentrations of organophosphate insecticides. Neurotoxicology 43:110\u2013116. https:\/\/doi.org\/10.1016\/j.neuro.2014.01.008","journal-title":"Neurotoxicology"},{"issue":"8","key":"1303_CR54","doi-asserted-by":"publisher","first-page":"5650","DOI":"10.1074\/jbc.M009179200","volume":"276","author":"T Meyer","year":"2001","unstructured":"Meyer T, Wellner-Kienitz MC, Biewald A, Bender K, Eickel A, Pott L (2001) Depletion of phosphatidylinositol 4,5-bisphosphate by activation of phospholipase C-coupled receptors causes slow inhibition but not desensitization of G protein-gated inward rectifier K+ current in atrial myocytes. J Biol Chem 276(8):5650\u20135658. https:\/\/doi.org\/10.1074\/jbc.M009179200","journal-title":"J Biol Chem"},{"issue":"4","key":"1303_CR55","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/s0143-4160(97)90064-6","volume":"22","author":"M Naraghi","year":"1997","unstructured":"Naraghi M (1997) T-jump study of calcium binding kinetics of calcium chelators. Cell Calcium 22(4):255\u2013268. https:\/\/doi.org\/10.1016\/s0143-4160(97)90064-6","journal-title":"Cell Calcium"},{"issue":"5\u20136","key":"1303_CR56","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1016\/s0143-4160(98)90058-6","volume":"24","author":"E Neher","year":"1998","unstructured":"Neher E (1998) Usefulness and limitations of linear approximations to the understanding of Ca++ signals. Cell Calcium 24(5\u20136):345\u2013357. https:\/\/doi.org\/10.1016\/s0143-4160(98)90058-6","journal-title":"Cell Calcium"},{"issue":"5","key":"1303_CR57","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1016\/j.neuron.2014.07.042","volume":"83","author":"Y Qi","year":"2014","unstructured":"Qi Y, Wang J, Bomben VC, Li DP, Chen SR, Sun H, Xi Y, Reed JG, Cheng J, Pan HL, Noebels JL, Yeh ET (2014) Hyper-SUMOylation of the Kv7 potassium channel diminishes the M-current leading to seizures and sudden death. Neuron 83(5):1159\u20131171. https:\/\/doi.org\/10.1016\/j.neuron.2014.07.042","journal-title":"Neuron"},{"issue":"8","key":"1303_CR58","doi-asserted-by":"publisher","first-page":"6075","DOI":"10.1074\/jbc.M204702200","volume":"278","author":"M Rajebhosale","year":"2003","unstructured":"Rajebhosale M, Greenwood S, Vidugiriene J, Jeromin A, Hilfiker S (2003) Phosphatidylinositol 4-OH kinase is a downstream target of neuronal calcium sensor-1 in enhancing exocytosis in neuroendocrine cells. J Biol Chem 278(8):6075\u20136084. https:\/\/doi.org\/10.1074\/jbc.M204702200","journal-title":"J Biol Chem"},{"issue":"30","key":"1303_CR59","doi-asserted-by":"publisher","first-page":"7950","DOI":"10.1523\/JNEUROSCI.2138-06.2006","volume":"26","author":"J Robbins","year":"2006","unstructured":"Robbins J, Marsh SJ, Brown DA (2006) Probing the regulation of M (Kv7) potassium channels in intact neurons with membrane-targeted peptides. J Neurosci 26(30):7950\u20137961. https:\/\/doi.org\/10.1523\/JNEUROSCI.2138-06.2006","journal-title":"J Neurosci"},{"issue":"6712","key":"1303_CR60","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1038\/25367","volume":"396","author":"BC Schroeder","year":"1998","unstructured":"Schroeder BC, Kubisch C, Stein V, Jentsch TJ (1998) Moderate loss of function of cyclic-AMP-modulated KCNQ2\/KCNQ3 K+ channels causes epilepsy. Nature 396(6712):687\u2013690. https:\/\/doi.org\/10.1038\/25367","journal-title":"Nature"},{"issue":"1","key":"1303_CR61","doi-asserted-by":"publisher","first-page":"C73","DOI":"10.1152\/ajpcell.00146.2008","volume":"295","author":"F Schuetz","year":"2008","unstructured":"Schuetz F, Kumar S, Poronnik P, Adams DJ (2008) Regulation of the voltage-gated K(+) channels KCNQ2\/3 and KCNQ3\/5 by serum- and glucocorticoid-regulated kinase-1. Am J Physiol Cell Physiol 295(1):C73-80. https:\/\/doi.org\/10.1152\/ajpcell.00146.2008","journal-title":"Am J Physiol Cell Physiol"},{"issue":"4","key":"1303_CR62","doi-asserted-by":"publisher","first-page":"2592","DOI":"10.1523\/JNEUROSCI.15-04-02592.1995","volume":"15","author":"KJ Seymour-Laurent","year":"1995","unstructured":"Seymour-Laurent KJ, Barish ME (1995) Inositol 1,4,5-trisphosphate and ryanodine receptor distributions and patterns of acetylcholine- and caffeine-induced calcium release in cultured mouse hippocampal neurons. J Neurosci 15(4):2592\u20132608","journal-title":"J Neurosci"},{"issue":"5","key":"1303_CR63","doi-asserted-by":"publisher","first-page":"1710","DOI":"10.1523\/JNEUROSCI.20-05-01710.2000","volume":"20","author":"MS Shapiro","year":"2000","unstructured":"Shapiro MS, Roche JP, Kaftan EJ, Cruzblanca H, Mackie K, Hille B (2000) Reconstitution of muscarinic modulation of the KCNQ2\/KCNQ3 K(+) channels that underlie the neuronal M current. J Neurosci 20(5):1710\u20131721","journal-title":"J Neurosci"},{"issue":"Pt 3","key":"1303_CR64","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1113\/jphysiol.2007.137265","volume":"582","author":"JW Sohn","year":"2007","unstructured":"Sohn JW, Lim A, Lee SH, Ho WK (2007) Decrease in PIP(2) channel interactions is the final common mechanism involved in PKC- and arachidonic acid-mediated inhibitions of GABA(B)-activated K+ current. J Physiol 582(Pt 3):1037\u20131046. https:\/\/doi.org\/10.1113\/jphysiol.2007.137265","journal-title":"J Physiol"},{"issue":"3","key":"1303_CR65","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1016\/s0896-6273(02)00790-0","volume":"35","author":"BC Suh","year":"2002","unstructured":"Suh BC, Hille B (2002) Recovery from muscarinic modulation of M current channels requires phosphatidylinositol 4,5-bisphosphate synthesis. Neuron 35(3):507\u2013520. https:\/\/doi.org\/10.1016\/s0896-6273(02)00790-0","journal-title":"Neuron"},{"issue":"5804","key":"1303_CR66","doi-asserted-by":"publisher","first-page":"1454","DOI":"10.1126\/science.1131163","volume":"314","author":"BC Suh","year":"2006","unstructured":"Suh BC, Inoue T, Meyer T, Hille B (2006) Rapid chemically induced changes of PtdIns(4,5)P2 gate KCNQ ion channels. Science 314(5804):1454\u20131457. https:\/\/doi.org\/10.1126\/science.1131163","journal-title":"Science"},{"issue":"Pt 20","key":"1303_CR67","doi-asserted-by":"publisher","first-page":"3909","DOI":"10.1242\/jcs.00072","volume":"115","author":"E Taverna","year":"2002","unstructured":"Taverna E, Francolini M, Jeromin A, Hilfiker S, Roder J, Rosa P (2002) Neuronal calcium sensor 1 and phosphatidylinositol 4-OH kinase beta interact in neuronal cells and are translocated to membranes during nucleotide-evoked exocytosis. J Cell Sci 115(Pt 20):3909\u20133922. https:\/\/doi.org\/10.1242\/jcs.00072","journal-title":"J Cell Sci"},{"issue":"10","key":"1303_CR68","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1016\/0166-2236(88)90194-4","volume":"11","author":"RW Tsien","year":"1988","unstructured":"Tsien RW, Lipscombe D, Madison DV, Bley KR, Fox AP (1988) Multiple types of neuronal calcium channels and their selective modulation. Trends Neurosci 11(10):431\u2013438. https:\/\/doi.org\/10.1016\/0166-2236(88)90194-4","journal-title":"Trends Neurosci"},{"issue":"9","key":"1303_CR69","doi-asserted-by":"publisher","first-page":"3257","DOI":"10.1091\/mbc.e02-04-0231","volume":"13","author":"J van Rheenen","year":"2002","unstructured":"van Rheenen J, Jalink K (2002) Agonist-induced PIP(2) hydrolysis inhibits cortical actin dynamics: regulation at a global but not at a micrometer scale. Mol Biol Cell 13(9):3257\u20133267. https:\/\/doi.org\/10.1091\/mbc.e02-04-0231","journal-title":"Mol Biol Cell"},{"issue":"5395","key":"1303_CR70","doi-asserted-by":"publisher","first-page":"1890","DOI":"10.1126\/science.282.5395.1890","volume":"282","author":"HS Wang","year":"1998","unstructured":"Wang HS, Pan Z, Shi W, Brown BS, Wymore RS, Cohen IS, Dixon JE, McKinnon D (1998) KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science 282(5395):1890\u20131893. https:\/\/doi.org\/10.1126\/science.282.5395.1890","journal-title":"Science"},{"issue":"13","key":"1303_CR71","doi-asserted-by":"publisher","first-page":"3400","DOI":"10.1523\/JNEUROSCI.3231-04.2005","volume":"25","author":"JS Winks","year":"2005","unstructured":"Winks JS, Hughes S, Filippov AK, Tatulian L, Abogadie FC, Brown DA, Marsh SJ (2005) Relationship between membrane phosphatidylinositol-4,5-bisphosphate and receptor-mediated inhibition of native neuronal M channels. J Neurosci 25(13):3400\u20133413. https:\/\/doi.org\/10.1523\/JNEUROSCI.3231-04.2005","journal-title":"J Neurosci"},{"key":"1303_CR72","volume-title":"Signaling mechanism of M current inhibition by M1 muscrinic receptor in rat sympathetic neurons","author":"J-Y Yoon","year":"2010","unstructured":"Yoon J-Y (2010) Signaling mechanism of M current inhibition by M1 muscrinic receptor in rat sympathetic neurons. Seoul National University, Seoul, Korea"},{"issue":"33","key":"1303_CR73","doi-asserted-by":"publisher","first-page":"8914","DOI":"10.1523\/JNEUROSCI.1739-07.2007","volume":"27","author":"O Zaika","year":"2007","unstructured":"Zaika O, Tolstykh GP, Jaffe DB, Shapiro MS (2007) Inositol triphosphate-mediated Ca2+ signals direct purinergic P2Y receptor regulation of neuronal ion channels. J Neurosci 27(33):8914\u20138926. https:\/\/doi.org\/10.1523\/JNEUROSCI.1739-07.2007","journal-title":"J Neurosci"},{"issue":"1","key":"1303_CR74","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1074\/jbc.M110.166033","volume":"286","author":"O Zaika","year":"2011","unstructured":"Zaika O, Zhang J, Shapiro MS (2011) Combined phosphoinositide and Ca2+ signals mediating receptor specificity toward neuronal Ca2+ channels. J Biol Chem 286(1):830\u2013841. https:\/\/doi.org\/10.1074\/jbc.M110.166033","journal-title":"J Biol Chem"},{"issue":"6","key":"1303_CR75","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1016\/s0896-6273(03)00125-9","volume":"37","author":"H Zhang","year":"2003","unstructured":"Zhang H, Craciun LC, Mirshahi T, Rohacs T, Lopes CM, Jin T, Logothetis DE (2003) PIP(2) activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents. Neuron 37(6):963\u2013975. https:\/\/doi.org\/10.1016\/s0896-6273(03)00125-9","journal-title":"Neuron"},{"issue":"43","key":"1303_CR76","doi-asserted-by":"publisher","first-page":"40183","DOI":"10.1074\/jbc.M104048200","volume":"276","author":"X Zhao","year":"2001","unstructured":"Zhao X, Varnai P, Tuymetova G, Balla A, Toth ZE, Oker-Blom C, Roder J, Jeromin A, Balla T (2001) Interaction of neuronal calcium sensor-1 (NCS-1) with phosphatidylinositol 4-kinase beta stimulates lipid kinase activity and affects membrane trafficking in COS-7 cells. J Biol Chem 276(43):40183\u201340189. https:\/\/doi.org\/10.1074\/jbc.M104048200","journal-title":"J Biol Chem"}],"container-title":["Cellular and Molecular Neurobiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10571-022-01303-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10571-022-01303-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10571-022-01303-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T00:39:59Z","timestamp":1728347999000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10571-022-01303-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,11]]},"references-count":76,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2023,7]]}},"alternative-id":["1303"],"URL":"https:\/\/doi.org\/10.1007\/s10571-022-01303-7","relation":{},"ISSN":["0272-4340","1573-6830"],"issn-type":[{"value":"0272-4340","type":"print"},{"value":"1573-6830","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,11]]},"assertion":[{"value":"1 March 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 October 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 November 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This study was reviewed and carried out in accordance with the Institutional Animal Care and Use Committee (IACUC) at Sungkyunkwan University School of Medicine (SUSM).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}}]}}