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Pathway Description
Proparacaine Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2013-08-22
Last Updated: 2019-08-16
Proparacaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Proparacaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore proparacaine preferentially inhibits neurons that are actively firing.
References
Proparacaine Pathway References
Harmatz A: Local anesthetics: uses and toxicities. Surg Clin North Am. 2009 Jun;89(3):587-98. doi: 10.1016/j.suc.2009.03.008.
Pubmed: 19465198
Skidmore RA, Patterson JD, Tomsick RS: Local anesthetics. Dermatol Surg. 1996 Jun;22(6):511-22; quiz 523-4.
Pubmed: 8646465
Rabert DK, Koch BD, Ilnicka M, Obernolte RA, Naylor SL, Herman RC, Eglen RM, Hunter JC, Sangameswaran L: A tetrodotoxin-resistant voltage-gated sodium channel from human dorsal root ganglia, hPN3/SCN10A. Pain. 1998 Nov;78(2):107-14. doi: 10.1016/s0304-3959(98)00120-1.
Pubmed: 9839820
Muzny DM, Scherer SE, Kaul R, Wang J, Yu J, Sudbrak R, Buhay CJ, Chen R, Cree A, Ding Y, Dugan-Rocha S, Gill R, Gunaratne P, Harris RA, Hawes AC, Hernandez J, Hodgson AV, Hume J, Jackson A, Khan ZM, Kovar-Smith C, Lewis LR, Lozado RJ, Metzker ML, Milosavljevic A, Miner GR, Morgan MB, Nazareth LV, Scott G, Sodergren E, Song XZ, Steffen D, Wei S, Wheeler DA, Wright MW, Worley KC, Yuan Y, Zhang Z, Adams CQ, Ansari-Lari MA, Ayele M, Brown MJ, Chen G, Chen Z, Clendenning J, Clerc-Blankenburg KP, Chen R, Chen Z, Davis C, Delgado O, Dinh HH, Dong W, Draper H, Ernst S, Fu G, Gonzalez-Garay ML, Garcia DK, Gillett W, Gu J, Hao B, Haugen E, Havlak P, He X, Hennig S, Hu S, Huang W, Jackson LR, Jacob LS, Kelly SH, Kube M, Levy R, Li Z, Liu B, Liu J, Liu W, Lu J, Maheshwari M, Nguyen BV, Okwuonu GO, Palmeiri A, Pasternak S, Perez LM, Phelps KA, Plopper FJ, Qiang B, Raymond C, Rodriguez R, Saenphimmachak C, Santibanez J, Shen H, Shen Y, Subramanian S, Tabor PE, Verduzco D, Waldron L, Wang J, Wang J, Wang Q, Williams GA, Wong GK, Yao Z, Zhang J, Zhang X, Zhao G, Zhou J, Zhou Y, Nelson D, Lehrach H, Reinhardt R, Naylor SL, Yang H, Olson M, Weinstock G, Gibbs RA: The DNA sequence, annotation and analysis of human chromosome 3. Nature. 2006 Apr 27;440(7088):1194-8. doi: 10.1038/nature04728.
Pubmed: 16641997
Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin ML, Teague J, Bignell G, Butler A, Cho J, Dalgliesh GL, Galappaththige D, Greenman C, Hardy C, Jia M, Latimer C, Lau KW, Marshall J, McLaren S, Menzies A, Mudie L, Stebbings L, Largaespada DA, Wessels LF, Richard S, Kahnoski RJ, Anema J, Tuveson DA, Perez-Mancera PA, Mustonen V, Fischer A, Adams DJ, Rust A, Chan-on W, Subimerb C, Dykema K, Furge K, Campbell PJ, Teh BT, Stratton MR, Futreal PA: Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature. 2011 Jan 27;469(7331):539-42. doi: 10.1038/nature09639. Epub 2011 Jan 19.
Pubmed: 21248752
Makita N, Sloan-Brown K, Weghuis DO, Ropers HH, George AL Jr: Genomic organization and chromosomal assignment of the human voltage-gated Na+ channel beta 1 subunit gene (SCN1B). Genomics. 1994 Oct;23(3):628-34. doi: 10.1006/geno.1994.1551.
Pubmed: 7851891
Patino GA, Claes LR, Lopez-Santiago LF, Slat EA, Dondeti RS, Chen C, O'Malley HA, Gray CB, Miyazaki H, Nukina N, Oyama F, De Jonghe P, Isom LL: A functional null mutation of SCN1B in a patient with Dravet syndrome. J Neurosci. 2009 Aug 26;29(34):10764-78. doi: 10.1523/JNEUROSCI.2475-09.2009.
Pubmed: 19710327
Baroni D, Picco C, Moran O: A mutation of SCN1B associated with GEFS+ causes functional and maturation defects of the voltage-dependent sodium channel. Hum Mutat. 2018 Oct;39(10):1402-1415. doi: 10.1002/humu.23589. Epub 2018 Jul 30.
Pubmed: 29992740
Denier C, Ducros A, Durr A, Eymard B, Chassande B, Tournier-Lasserve E: Missense CACNA1A mutation causing episodic ataxia type 2. Arch Neurol. 2001 Feb;58(2):292-5. doi: 10.1001/archneur.58.2.292.
Pubmed: 11176968
Hans M, Urrutia A, Deal C, Brust PF, Stauderman K, Ellis SB, Harpold MM, Johnson EC, Williams ME: Structural elements in domain IV that influence biophysical and pharmacological properties of human alpha1A-containing high-voltage-activated calcium channels. Biophys J. 1999 Mar;76(3):1384-400. doi: 10.1016/S0006-3495(99)77300-5.
Pubmed: 10049321
Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR: Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell. 1996 Nov 1;87(3):543-52. doi: 10.1016/s0092-8674(00)81373-2.
Pubmed: 8898206
Powers PA, Liu S, Hogan K, Gregg RG: Skeletal muscle and brain isoforms of a beta-subunit of human voltage-dependent calcium channels are encoded by a single gene. J Biol Chem. 1992 Nov 15;267(32):22967-72.
Pubmed: 1385409
Williams ME, Feldman DH, McCue AF, Brenner R, Velicelebi G, Ellis SB, Harpold MM: Structure and functional expression of alpha 1, alpha 2, and beta subunits of a novel human neuronal calcium channel subtype. Neuron. 1992 Jan;8(1):71-84. doi: 10.1016/0896-6273(92)90109-q.
Pubmed: 1309651
Collin T, Wang JJ, Nargeot J, Schwartz A: Molecular cloning of three isoforms of the L-type voltage-dependent calcium channel beta subunit from normal human heart. Circ Res. 1993 Jun;72(6):1337-44. doi: 10.1161/01.res.72.6.1337.
Pubmed: 7916667
Klugbauer N, Lacinova L, Marais E, Hobom M, Hofmann F: Molecular diversity of the calcium channel alpha2delta subunit. J Neurosci. 1999 Jan 15;19(2):684-91.
Pubmed: 9880589
Gao B, Sekido Y, Maximov A, Saad M, Forgacs E, Latif F, Wei MH, Lerman M, Lee JH, Perez-Reyes E, Bezprozvanny I, Minna JD: Functional properties of a new voltage-dependent calcium channel alpha(2)delta auxiliary subunit gene (CACNA2D2). J Biol Chem. 2000 Apr 21;275(16):12237-42. doi: 10.1074/jbc.275.16.12237.
Pubmed: 10766861
Hobom M, Dai S, Marais E, Lacinova L, Hofmann F, Klugbauer N: Neuronal distribution and functional characterization of the calcium channel alpha2delta-2 subunit. Eur J Neurosci. 2000 Apr;12(4):1217-26. doi: 10.1046/j.1460-9568.2000.01009.x.
Pubmed: 10762351
Kong W, Po S, Yamagishi T, Ashen MD, Stetten G, Tomaselli GF: Isolation and characterization of the human gene encoding Ito: further diversity by alternative mRNA splicing. Am J Physiol. 1998 Dec;275(6):H1963-70. doi: 10.1152/ajpheart.1998.275.6.H1963.
Pubmed: 9843794
Kikuno R, Nagase T, Ishikawa K, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O: Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 1999 Jun 30;6(3):197-205. doi: 10.1093/dnares/6.3.197.
Pubmed: 10470851
Zhu XR, Wulf A, Schwarz M, Isbrandt D, Pongs O: Characterization of human Kv4.2 mediating a rapidly-inactivating transient voltage-sensitive K+ current. Receptors Channels. 1999;6(5):387-400.
Pubmed: 10551270
Bahring R, Dannenberg J, Peters HC, Leicher T, Pongs O, Isbrandt D: Conserved Kv4 N-terminal domain critical for effects of Kv channel-interacting protein 2.2 on channel expression and gating. J Biol Chem. 2001 Jun 29;276(26):23888-94. doi: 10.1074/jbc.M101320200. Epub 2001 Apr 3.
Pubmed: 11287421
An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, Hinson JW, Mattsson KI, Strassle BW, Trimmer JS, Rhodes KJ: Modulation of A-type potassium channels by a family of calcium sensors. Nature. 2000 Feb 3;403(6769):553-6. doi: 10.1038/35000592.
Pubmed: 10676964
Ohya S, Morohashi Y, Muraki K, Tomita T, Watanabe M, Iwatsubo T, Imaizumi Y: Molecular cloning and expression of the novel splice variants of K(+) channel-interacting protein 2. Biochem Biophys Res Commun. 2001 Mar 23;282(1):96-102. doi: 10.1006/bbrc.2001.4558.
Pubmed: 11263977
Neuron Function References
Lovinger DM: Communication networks in the brain: neurons, receptors, neurotransmitters, and alcohol. Alcohol Res Health. 2008;31(3):196-214.
Pubmed: 23584863
Kress GJ, Mennerick S: Action potential initiation and propagation: upstream influences on neurotransmission. Neuroscience. 2009 Jan 12;158(1):211-22. doi: 10.1016/j.neuroscience.2008.03.021. Epub 2008 Mar 19.
Pubmed: 18472347
Platkiewicz J, Brette R: A threshold equation for action potential initiation. PLoS Comput Biol. 2010 Jul 8;6(7):e1000850. doi: 10.1371/journal.pcbi.1000850.
Pubmed: 20628619
Rabert DK, Koch BD, Ilnicka M, Obernolte RA, Naylor SL, Herman RC, Eglen RM, Hunter JC, Sangameswaran L: A tetrodotoxin-resistant voltage-gated sodium channel from human dorsal root ganglia, hPN3/SCN10A. Pain. 1998 Nov;78(2):107-14. doi: 10.1016/s0304-3959(98)00120-1.
Pubmed: 9839820
Muzny DM, Scherer SE, Kaul R, Wang J, Yu J, Sudbrak R, Buhay CJ, Chen R, Cree A, Ding Y, Dugan-Rocha S, Gill R, Gunaratne P, Harris RA, Hawes AC, Hernandez J, Hodgson AV, Hume J, Jackson A, Khan ZM, Kovar-Smith C, Lewis LR, Lozado RJ, Metzker ML, Milosavljevic A, Miner GR, Morgan MB, Nazareth LV, Scott G, Sodergren E, Song XZ, Steffen D, Wei S, Wheeler DA, Wright MW, Worley KC, Yuan Y, Zhang Z, Adams CQ, Ansari-Lari MA, Ayele M, Brown MJ, Chen G, Chen Z, Clendenning J, Clerc-Blankenburg KP, Chen R, Chen Z, Davis C, Delgado O, Dinh HH, Dong W, Draper H, Ernst S, Fu G, Gonzalez-Garay ML, Garcia DK, Gillett W, Gu J, Hao B, Haugen E, Havlak P, He X, Hennig S, Hu S, Huang W, Jackson LR, Jacob LS, Kelly SH, Kube M, Levy R, Li Z, Liu B, Liu J, Liu W, Lu J, Maheshwari M, Nguyen BV, Okwuonu GO, Palmeiri A, Pasternak S, Perez LM, Phelps KA, Plopper FJ, Qiang B, Raymond C, Rodriguez R, Saenphimmachak C, Santibanez J, Shen H, Shen Y, Subramanian S, Tabor PE, Verduzco D, Waldron L, Wang J, Wang J, Wang Q, Williams GA, Wong GK, Yao Z, Zhang J, Zhang X, Zhao G, Zhou J, Zhou Y, Nelson D, Lehrach H, Reinhardt R, Naylor SL, Yang H, Olson M, Weinstock G, Gibbs RA: The DNA sequence, annotation and analysis of human chromosome 3. Nature. 2006 Apr 27;440(7088):1194-8. doi: 10.1038/nature04728.
Pubmed: 16641997
Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin ML, Teague J, Bignell G, Butler A, Cho J, Dalgliesh GL, Galappaththige D, Greenman C, Hardy C, Jia M, Latimer C, Lau KW, Marshall J, McLaren S, Menzies A, Mudie L, Stebbings L, Largaespada DA, Wessels LF, Richard S, Kahnoski RJ, Anema J, Tuveson DA, Perez-Mancera PA, Mustonen V, Fischer A, Adams DJ, Rust A, Chan-on W, Subimerb C, Dykema K, Furge K, Campbell PJ, Teh BT, Stratton MR, Futreal PA: Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature. 2011 Jan 27;469(7331):539-42. doi: 10.1038/nature09639. Epub 2011 Jan 19.
Pubmed: 21248752
Makita N, Sloan-Brown K, Weghuis DO, Ropers HH, George AL Jr: Genomic organization and chromosomal assignment of the human voltage-gated Na+ channel beta 1 subunit gene (SCN1B). Genomics. 1994 Oct;23(3):628-34. doi: 10.1006/geno.1994.1551.
Pubmed: 7851891
Patino GA, Claes LR, Lopez-Santiago LF, Slat EA, Dondeti RS, Chen C, O'Malley HA, Gray CB, Miyazaki H, Nukina N, Oyama F, De Jonghe P, Isom LL: A functional null mutation of SCN1B in a patient with Dravet syndrome. J Neurosci. 2009 Aug 26;29(34):10764-78. doi: 10.1523/JNEUROSCI.2475-09.2009.
Pubmed: 19710327
Baroni D, Picco C, Moran O: A mutation of SCN1B associated with GEFS+ causes functional and maturation defects of the voltage-dependent sodium channel. Hum Mutat. 2018 Oct;39(10):1402-1415. doi: 10.1002/humu.23589. Epub 2018 Jul 30.
Pubmed: 29992740
Denier C, Ducros A, Durr A, Eymard B, Chassande B, Tournier-Lasserve E: Missense CACNA1A mutation causing episodic ataxia type 2. Arch Neurol. 2001 Feb;58(2):292-5. doi: 10.1001/archneur.58.2.292.
Pubmed: 11176968
Hans M, Urrutia A, Deal C, Brust PF, Stauderman K, Ellis SB, Harpold MM, Johnson EC, Williams ME: Structural elements in domain IV that influence biophysical and pharmacological properties of human alpha1A-containing high-voltage-activated calcium channels. Biophys J. 1999 Mar;76(3):1384-400. doi: 10.1016/S0006-3495(99)77300-5.
Pubmed: 10049321
Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR: Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell. 1996 Nov 1;87(3):543-52. doi: 10.1016/s0092-8674(00)81373-2.
Pubmed: 8898206
Powers PA, Liu S, Hogan K, Gregg RG: Skeletal muscle and brain isoforms of a beta-subunit of human voltage-dependent calcium channels are encoded by a single gene. J Biol Chem. 1992 Nov 15;267(32):22967-72.
Pubmed: 1385409
Williams ME, Feldman DH, McCue AF, Brenner R, Velicelebi G, Ellis SB, Harpold MM: Structure and functional expression of alpha 1, alpha 2, and beta subunits of a novel human neuronal calcium channel subtype. Neuron. 1992 Jan;8(1):71-84. doi: 10.1016/0896-6273(92)90109-q.
Pubmed: 1309651
Collin T, Wang JJ, Nargeot J, Schwartz A: Molecular cloning of three isoforms of the L-type voltage-dependent calcium channel beta subunit from normal human heart. Circ Res. 1993 Jun;72(6):1337-44. doi: 10.1161/01.res.72.6.1337.
Pubmed: 7916667
Klugbauer N, Lacinova L, Marais E, Hobom M, Hofmann F: Molecular diversity of the calcium channel alpha2delta subunit. J Neurosci. 1999 Jan 15;19(2):684-91.
Pubmed: 9880589
Gao B, Sekido Y, Maximov A, Saad M, Forgacs E, Latif F, Wei MH, Lerman M, Lee JH, Perez-Reyes E, Bezprozvanny I, Minna JD: Functional properties of a new voltage-dependent calcium channel alpha(2)delta auxiliary subunit gene (CACNA2D2). J Biol Chem. 2000 Apr 21;275(16):12237-42. doi: 10.1074/jbc.275.16.12237.
Pubmed: 10766861
Hobom M, Dai S, Marais E, Lacinova L, Hofmann F, Klugbauer N: Neuronal distribution and functional characterization of the calcium channel alpha2delta-2 subunit. Eur J Neurosci. 2000 Apr;12(4):1217-26. doi: 10.1046/j.1460-9568.2000.01009.x.
Pubmed: 10762351
Kong W, Po S, Yamagishi T, Ashen MD, Stetten G, Tomaselli GF: Isolation and characterization of the human gene encoding Ito: further diversity by alternative mRNA splicing. Am J Physiol. 1998 Dec;275(6):H1963-70. doi: 10.1152/ajpheart.1998.275.6.H1963.
Pubmed: 9843794
Kikuno R, Nagase T, Ishikawa K, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O: Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 1999 Jun 30;6(3):197-205. doi: 10.1093/dnares/6.3.197.
Pubmed: 10470851
Zhu XR, Wulf A, Schwarz M, Isbrandt D, Pongs O: Characterization of human Kv4.2 mediating a rapidly-inactivating transient voltage-sensitive K+ current. Receptors Channels. 1999;6(5):387-400.
Pubmed: 10551270
Bahring R, Dannenberg J, Peters HC, Leicher T, Pongs O, Isbrandt D: Conserved Kv4 N-terminal domain critical for effects of Kv channel-interacting protein 2.2 on channel expression and gating. J Biol Chem. 2001 Jun 29;276(26):23888-94. doi: 10.1074/jbc.M101320200. Epub 2001 Apr 3.
Pubmed: 11287421
An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, Hinson JW, Mattsson KI, Strassle BW, Trimmer JS, Rhodes KJ: Modulation of A-type potassium channels by a family of calcium sensors. Nature. 2000 Feb 3;403(6769):553-6. doi: 10.1038/35000592.
Pubmed: 10676964
Ohya S, Morohashi Y, Muraki K, Tomita T, Watanabe M, Iwatsubo T, Imaizumi Y: Molecular cloning and expression of the novel splice variants of K(+) channel-interacting protein 2. Biochem Biophys Res Commun. 2001 Mar 23;282(1):96-102. doi: 10.1006/bbrc.2001.4558.
Pubmed: 11263977
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