Pharmacology Pharmacology

Required Reading

K+ Selectivity and Gating by Gproteins, Calcium – KcsA, GIRK, MthK


Shimizu, H., Iwamoto, M., Konno, T., Nihei, A., Sasaki, Y.C., and Oiki, S. (2008). Global twisting motion of single molecular KcsA potassium channel upon gating. Cell 132, 67-78.

Nishida M, MacKinnon R (2002) Structural basis of inward rectification: cytoplasmic pore of the G protein-gated inward rectifier GIRK1 at 1.8 A resolution. Cell 111:957-965.

Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R (1998) The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280:69-77.


Chakrapani, S., and Perozo, E. (2007). How to gate an ion channel: lessons from MthK. Nature structural & molecular biology 14, 180-182.

Swartz, K. J. (2004). Towards a structural view of gating in potassium channels. Nat Rev Neurosci 5, 905-916.

Bichet, D., Haass, F.A., and Jan, L.Y. (2003). Merging functional studies with structures of inward-rectifier K(+) channels. Nat Rev Neurosci 4, 957-967.


Thompson, A.N., Posson, D.J., Parsa, P.V., and Nimigean, C.M. (2008). Molecular mechanism of pH sensing in KcsA potassium channels. Proc Natl Acad Sci U S A 105, 6900-6905.

Jiang Y, Lee A, Chen J, Cadene M, Chait BT, MacKinnon R (2002a) The open pore conformation of potassium channels. Nature 417:523-526.

Valiyaveetil FI, Zhou Y, MacKinnon R (2002) Lipids in the structure, folding, and function of the KcsA K+ channel. Biochemistry 41:10771-10777.

Roux B, MacKinnon R (1999) The cavity and pore helices in the KcsA K+ channel: electrostatic stabilization of monovalent cations. Science 285:100-102.

Riven, I., Iwanir, S., and Reuveny, E. (2006). GIRK channel activation involves a local rearrangement of a preformed G protein channel complex. Neuron 51, 561-573.

Kuo A, Gulbis JM, Antcliff JF, Rahman T, Lowe ED, Zimmer J, Cuthbertson J, Ashcroft FM, Ezaki T, Doyle DA (2003) Crystal structure of the potassium channel KirBac1.1 in the closed state. Science 300:1922-1926.

Ye, S., Li, Y., Chen, L., and Jiang, Y. (2006). Crystal structures of a ligand-free MthK gating ring: insights into the ligand gating mechanism of K+ channels. Cell 126, 1161-1173.

Jiang Y, Lee A, Chen J, Cadene M, Chait BT, MacKinnon R (2002b) Crystal structure and mechanism of a calcium-gated potassium channel. Nature 417:515-522.

Jiang Y, Pico A, Cadene M, Chait BT, MacKinnon R (2001) Structure of the RCK domain from the E. coli K+ channel and demonstration of its presence in the human BK channel. Neuron 29:593-601.

Voltage Gating – Kv1.2 and KsAP


Lee, S.Y., Banerjee, A., and MacKinnon, R. (2009). Two separate interfaces between the voltage sensor and pore are required for the function of voltage-dependent K(+) channels. PLoS biology 7, e47.

Wang, L., and Sigworth, F.J. (2009). Structure of the BK potassium channel in a lipid membrane from electron cryomicroscopy. Nature 461, 292-295.

Long, S.B., Tao, X., Campbell, E.B., and MacKinnon, R. (2007). Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature 450, 376-382.


Swartz, K.J. (2008). Sensing voltage across lipid membranes. Nature 456, 891-897.


Vamvouka, M., Cieslak, J., Van Eps, N., Hubbell, W., and Gross, A. (2008). The structure of the lipid-embedded potassium channel voltage sensor determined by double-electron-electron resonance spectroscopy. Protein Sci 17, 506-517.

Pathak, M.M., Yarov-Yarovoy, V., Agarwal, G., Roux, B., Barth, P., Kohout, S., Tombola, F., and Isacoff, E.Y. (2007). Closing in on the resting state of the Shaker K(+) channel. Neuron 56, 124-140.

Tombola, F., Pathak, M.M., Gorostiza, P., and Isacoff, E.Y. (2007). The twisted ion-permeation pathway of a resting voltage-sensing domain. Nature 445, 546-549.

Long, S.B., Campbell, E.B., and Mackinnon, R. (2005). Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science 309, 897-903.

Tombola, F., Pathak, M. M., and Isacoff, E. Y. (2005). Voltage-sensing arginines in a potassium channel permeate and occlude cation-selective pores. Neuron 45, 379-388.

Gandhi, C. S., Clark, E., Loots, E., Pralle, A., and Isacoff, E. Y. (2003). The orientation and molecular movement of a K(+) channel voltage-sensing domain. Neuron 40, 515-525.

Jiang Y, Ruta V, Chen J, Lee A, MacKinnon R (2003a) The principle of gating charge movement in a voltage-dependent K+ channel. Nature 423:42-48.

Jiang Y, Lee A, Chen J, Ruta V, Cadene M, Chait BT, MacKinnon R (2003b) X-ray structure of a voltage-dependent K+ channel. Nature 423:33-41.

Laine M, Lin MC, Bannister JP, Silverman WR, Mock AF, Roux B, Papazian DM (2003) Atomic proximity between S4 segment and pore domain in Shaker potassium channels. Neuron 39:467-481.

Ruta V, Jiang Y, Lee A, Chen J, MacKinnon R (2003) Functional analysis of an archaebacterial voltage-dependent K+ channel. Nature 422:180-185.

Sodium Channel Mutations Causing Cardiac Arrhythmias

*indicate required reading


Ruan, Y., Liu, N., and Priori, S.G. (2009). Sodium channel mutations and arrhythmias. Nat Rev Cardiol 6, 337-348.

George, A.L., Jr. (2009). Genetic modulation of impaired cardiac conduction: sodium channel β4 subunit missing in action. Circ Res 104, 1238-1239. (Companion to Remme et al below)


*Remme, C.A., Scicluna, B.P., Verkerk, A.O., Amin, A.S., van Brunschot, S., Beekman, L., Deneer, V.H., Chevalier, C., Oyama, F., Miyazaki, H., et al. (2009). Genetically determined differences in sodium current characteristics modulate conduction disease severity in mice with cardiac sodium channelopathy. Circ Res 104, 1283-1292.

*Bezzina, C., Veldkamp, M.W., van Den Berg, M.P., Postma, A.V., Rook, M.B., Viersma, J.W., van Langen, I.M., Tan-Sindhunata, G., Bink-Boelkens, M.T., van Der Hout, A.H., et al. (1999). A single Na(+) channel mutation causing both long-QT and Brugada syndromes. Circ Res 85, 1206-1213.

*Nuyens, D., Stengl, M., Dugarmaa, S., Rossenbacker, T., Compernolle, V., Rudy, Y., Smits, J.F., Flameng, W., Clancy, C.E., Moons, L., et al. (2001). Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome. Nat Med 7, 1021-1027.

Rivolta, I., Abriel, H., Tateyama, M., Liu, H., Memmi, M., Vardas, P., Napolitano, C., Priori, S.G., and Kass, R.S. (2001). Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes. J Biol Chem 276, 30623-30630.

Bennett, P.B., Yazawa, K., Makita, N., and George, A.L., Jr. (1995). Molecular mechanism for an inherited cardiac arrhythmia. Nature 376, 683-685.

Wang, Q., Shen, J., Splawski, I., Atkinson, D., Li, Z., Robinson, J.L., Moss, A.J., Towbin, J.A., and Keating, M.T. (1995). SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80, 805-811.

Sodium Channel Mutations in Epilepsy

*indicate required reading


Catterall, W.A., Dib-Hajj, S., Meisler, M.H., and Pietrobon, D. (2008). Inherited neuronal ion channelopathies: new windows on complex neurological diseases. J Neurosci 28, 11768-11777.

Meisler, M.H., and Kearney, J.A. (2005). Sodium channel mutations in epilepsy and other neurological disorders. J Clin Invest 115, 2010-2017.

George, A.L., Jr. (2005). Inherited disorders of voltage-gated sodium channels. J Clin Invest 115, 1990-1999. 1180550.


*Tang, B., Dutt, K., Papale, L., Rusconi, R., Shankar, A., Hunter, J., Tufik, S., Yu, F.H., Catterall, W.A., Mantegazza, M., et al. (2009). A BAC transgenic mouse model reveals neuron subtype-specific effects of a Generalized Epilepsy with Febrile Seizures Plus (GEFS+) mutation. Neurobiol Dis. 35, 91-102.

Rusconi, R., Combi, R., Cestele, S., Grioni, D., Franceschetti, S., Dalpra, L., and Mantegazza, M. (2009). A rescuable folding defective Na(v)1.1 (SCN1A) sodium channel mutant causes GEFS+: Common mechanism in Na(v)1.1 related epilepsies? Hum Mutat. 30, E747-760.

*Rusconi, R., Scalmani, P., Cassulini, R.R., Giunti, G., Gambardella, A., Franceschetti, S., Annesi, G., Wanke, E., and Mantegazza, M. (2007). Modulatory proteins can rescue a trafficking defective epileptogenic Nav1.1 Na+ channel mutant. J Neurosci 27, 11037-11046.

*Barela, A.J., Waddy, S.P., Lickfett, J.G., Hunter, J., Anido, A., Helmers, S.L., Goldin, A.L., and Escayg, A. (2006). An epilepsy mutation in the sodium channel SCN1A that decreases channel excitability. J Neurosci 26, 2714-2723.

Rhodes, T.H., Vanoye, C.G., Ohmori, I., Ogiwara, I., Yamakawa, K., and George, A.L., Jr. (2005). Sodium channel dysfunction in intractable childhood epilepsy with generalized tonic-clonic seizures. J Physiol 569, 433-445. 1464244.

*Rhodes, T.H., Lossin, C., Vanoye, C.G., Wang, D.W., and George, A.L., Jr. (2004). Noninactivating voltage-gated sodium channels in severe myoclonic epilepsy of infancy. Proc Natl Acad Sci U S A 101, 11147-11152.

Ohmori, I., Ohtsuka, Y., Ouchida, M., Ogino, T., Maniwa, S., Shimizu, K., and Oka, E. (2003). Is phenotype difference in severe myoclonic epilepsy in infancy related to SCN1A mutations? Brain Dev 25, 488-493.

Meadows, L.S., Malhotra, J., Loukas, A., Thyagarajan, V., Kazen-Gillespie, K.A., Koopman, M.C., Kriegler, S., Isom, L.L., and Ragsdale, D.S. (2002). Functional and biochemical analysis of a sodium channel beta1 subunit mutation responsible for generalized epilepsy with febrile seizures plus type 1. J Neurosci 22, 10699-10709.

Claes, L., Del-Favero, J., Ceulemans, B., Lagae, L., Van Broeckhoven, C., and De Jonghe, P. (2001). De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet 68, 1327-1332.

Spampanato, J., Escayg, A., Meisler, M.H., and Goldin, A.L. (2001). Functional effects of two voltage-gated sodium channel mutations that cause generalized epilepsy with febrile seizures plus type 2. J Neurosci 21, 7481-7490.

Escayg, A., MacDonald, B.T., Meisler, M.H., Baulac, S., Huberfeld, G., An-Gourfinkel, I., Brice, A., LeGuern, E., Moulard, B., Chaigne, D., et al. (2000). Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nat Genet 24, 343-345.

Calcium Channelopathies (Week 5)

Overall Review

Lehmann-Horn F, Jurkat-Rott K. (1999) Voltage-gated ion channels and hereditary disease. Physiol. Rev. 79:1317-1372.

Calcium Channel Mutations in Cerebellar Ataxia


Kordasiewicz HB, Gomez CM. (2007) Molecular pathogenesis of spinocerebellar ataxia type 6. Neurotherapeutics 4:285-294.

Manto M, Marmolino D. (2009) Cerebellar ataxias. Curr Opin Neurol. 22:419-429.

Required Reading

Kordasiewicz HB, Thompson RM, Clark HB, Gomez CM. (2006) C-termini of P/Q-type Ca channel alpha1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity. Hum Mol Genet. 15:1587-1599.

Watase K, Barrett CF, Miyazaki T, Ishiguro T, Ishikawa K, Hu Y, Unno T, Sun Y, Kasai S, Watanabe M, Gomez CM, Mizusawa H, Tsien RW, Zoghbi HY. (2008) Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Cav2.1 channels. Proc Natl Acad Sci U S A. 105:11987-11992.

Mezghrani A, Monteil A, Watschinger K, Sinnegger-Brauns MJ, Barrère C, Bourinet E, Nargeot J, Striessnig J, Lory P. (2008) A destructive interaction mechanism accounts for dominant-negative effects of misfolded mutants of voltage-gated calcium channels. J Neurosci. 28:4501-4511.

Additional Background Articles

Ophoff RA, Terwindt GM, Vergouwe MN, van Eijke R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, and Frants RR (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the calcium channel gene CACNL1A4. Cell 87:543-552.

Zhuchenko, O., Bailey, J., Bonnen, P., Ashizawa, T., Stockton, D.W., Amos, C., Dobyns, W.B., Subramony, S.H., Zoghbi, H.Y., and Lee, C.C. (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α1A-voltage-dependent calcium channel. Nature Genet. 15:62-69.

Guida S, Trettel F, Pagnutti S, Mantuano E, Tottene A, Veneziano L, Fellin T, Spadaro M, Stauderman K, Williams M, Volsen S, Ophoff R, Frants R, Jodice C, Frontali M, Pietrobon D. (2001) Complete loss of P/Q calcium channel activity caused by a CACNA1A missense mutation carried by patients with episodic ataxia type 2. Am. J. Hum. Genet. 68:759-764.

Saegusa H, Wakamori M, Matsuda Y, Wang J, Mori Y, Zong S, Tanabe T. Properties of human Cav2.1 channel with a spinocerebellar ataxia type 6 mutation expressed in Purkinje cells. (2007) Mol Cell Neurosci. 34:261-270.

Ishikawa K, Owada K, Ishida K, Fujigasaki H, Shun Li M, Tsunemi T, Ohkoshi N, Toru S, Mizutani T, Hayashi M, Arai N, Hasegawa K, Kawanami T, Kato T, Makifuchi T, Shoji S, Tanabe T, Mizusawa H. (2001) Cytoplasmic and nuclear polyglutamine aggregates in SCA6 Purkinje cells. Neurology 56:1753-1756.

Calcium Channel Mutations in Familial Hemiplegic Migraine


Pietrobon D., and Striessnig, J. (2003) Neurobiology of migraine. Nature Rev. Neurosci. 4:386-398.

Pietrobon D. (2007) Familial hemiplegic migraine. Neurotherapeutics 4:274-284.

Required Reading

Tottene, A., Fellin, T., Pagnutti, S., Luvisetto, S., Striessnig, J., Fletcher, C., and Pietrobon, D. (2002) Familial hemiplegic migraine mutations increase calcium influx through single human Cav2.1 channels and decrease maximal Cav2.1 current density in neurons. Proc. Natl. Acad. Sci. USA 99:13284-13289.

van den Maagdenberg, A.M., Pietrobon, D., Pizzorusso, T., Kaja, S., Broos, L.A., Cesetti, T., van de Ven. R.C., Tottene, A., van der Kaa, J., Plomp, J.J., Frants, R.R., and Ferrari, M.D. (2004) A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 41:701-710.

Tottene A, Conti R, Fabbro A, Vecchia D, Shapovalova M, Santello M, van den Maagdenberg AM, Ferrari MD, Pietrobon D. (2009) Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading depression in Cav2.1 knockin migraine mice. Neuron 61:762-773.

Additional Background Articles

Kraus, R.L., Sinnegger, M.J., Glossmann, H., Hering, S., and Striessnig, J. (1998) Familial hemiplegic migraine mutations change a1A calcium channel kinetics. J. Biol. Chem. 273:5586-5590.

Hans, M., Luvisetto, S., Williams, M.E., Spagnolo, M., Urrutia, A., Tottene, A., Brust, P.F., Johnson, E.C., Harpold, M.M., Stauderman, K.A., and Pietrobon, D. (1999) Functional consequences of mutations in the human α1A calcium channel subunit linked to familial hemiplegic migraine. J. Neurosci. 19:1610-1619.

Kraus, R.L., Sinnegger, M.J., Koschak, A., Glossmann, H., Stenirri, S., Carrera, P., and Striessnig, J. (2000) Three new familial hemiplegic migraine mutants affect P/Q-type calcium channel kinetics. J. Biol. Chem. 275:9239-9243.

Tottene A, Pivotto F, Fellin T, Cesetti T, van den Maagdenberg AM, Pietrobon D.Specific kinetic alterations of human Cav2.1 calcium channels produced by mutation S218L causing familial hemiplegic migraine and delayed cerebral edema and coma after minor head trauma. (2005) J Biol Chem. 280:17678-17686.

Cao YQ, Tsien RW. (2005) Effects of familial hemiplegic migraine type 1 mutations on neuronal P/Qtype Ca channel activity and inhibitory synaptic transmission. Proc Natl Acad Sci U S A. 102:2590-2595.

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