Abstract
Current kinetics takes into account three key components of receptor function. They include an open or activated state, a deactivated state, and a desensitized state. As the ligand binds to the receptor, a conformational change takes place allowing pore formation and ion permeability, defining an activated state. The deactivated state refers to a receptor transitioning from a bound to an unbound agonist state with decreasing ionic permeability as the channel closes. This process occurs as the agonist concentration becomes zero. Finally, a desensitized state refers to a reduced response to an agonist often due to prolonged agonist exposure (i.e., the receptor is in a nonconducting state despite agonist being bound to the receptor). Desensitization can be altered by neurotransmitter clearance from the synaptic cleft via diffusion, degradation, or reuptake through transporters expressed on neuronal or glial cells. Prolonged exposure to neurotransmission may induce desensitization of receptors, while rapid removal of the neurotransmitter from the synaptic cleft may reduce desensitization.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
Notes
- 1.
There are two other key components to receptor function, which include inactivation and sensitization. When a channel/receptor loses permeability to an ion or is unable to activate downstream signaling processes in the presence of an agonist, it is considered inactive. An example is the “ball and chain” model of inactivation in which inactivation is caused by peptide (the ball) insertion into the open channel pore, thus blocking ion flow through the channel [1]. Sensitization, on the other hand, refers to a potentiated response to a given stimulus. For example, administration of an agonist at the same concentration previously used can trigger greater postsynaptic currents in sensitized receptors.
- 2.
In addition to GABAARs, there are GABACRs, which are mainly located in the retina and are composed of rho subunits. Since 2008, it is recommended that GABACRs become known as GABAA-ρ [88].
- 3.
During embryonic development and at birth, GABA Rs and GlyRs play different roles in regulating membrane potentials. Their activation elicits depolarization of membrane voltage causing the cell to become more excitable. This effect is due to the positive chloride equilibrium potential, which results in the efflux of chloride from the postsynaptic cell upon receptor activation.
References
Armstrong CM (1981) Sodium channels and gating currents. Physiol Rev 61(3):644–683
Barberis A, Mozrzymas JW, Ortinski PI, Vicini S (2007) Desensitization and binding proper- ties determine distinct alpha1beta2gamma2 and alpha3beta2gamma2 GABA(A) receptor- channel kinetic behavior. Eur J Neurosci 25(9):2726–2740
Bettler B, Boulter J, Hermans-Borgmeyer I, O’Shea-Greenfield A, Deneris ES, Moll C, Borgmeyer U, Hollmann M, Heinemann S (1990) Cloning of a novel glutamate receptor subunit, GluR5: expression in the nervous system during development. Neuron 5(5):583–595
Bettler B, Egebjerg J, Sharma G, Pecht G, Hermans-Borgmeyer I, Moll C, Stevens CF, Heinemann S (1992) Cloning of a putative glutamate receptor: a low affinity kainate-binding subunit. Neuron 8(2):257–265
Boulter J, Hollmann M, O’Shea-Greenfield A, Hartley M, Deneris E, Maron C, Heinemann S (1990) Molecular cloning and functional expression of glutamate receptor subunit genes. Science 249(4972):1033–1037
Egebjerg J, Bettler B, Hermans-Borgmeyer I, Heinemann S (1991) Cloning of a cDNA for a glutamate receptor subunit activated by kainate but not AMPA. Nature 351(6329):745–748
Herb A, Burnashev N, Werner P, Sakmann B, Wisden W, Seeburg PH (1992) The KA-2 subunit of excitatory amino acid receptors shows widespread expression in brain and forms ion channels with distantly related sub- units. Neuron 8(4):775–785
Keinanen K, Wisden W, Sommer B, Werner P, Herb A, Verdoorn TA, Sakmann B, Seeburg PH (1990) A family of AMPA- selective glutamate receptors. Science 249(4968):556–560
Morita T, Sakimura K, Kushiya E, Yamazaki M, Meguro H, Araki K, Abe T, Mori KJ, Mishina M (1992) Cloning and functional expression of a cDNA encoding the mouse beta 2 subunit of the kainate-selective gluta- mate receptor channel. Brain Res Mol Brain Res 14(1–2):143–146
Sakimura K, Morita T, Kushiya E, Mishina M (1992) Primary structure and expression of the gamma 2 subunit of the glutamate recep- tor channel selective for kainate. Neuron 8(2):267–274
Sommer B, Burnashev N, Verdoorn TA, Keinanen K, Sakmann B, Seeburg PH (1992) A glutamate receptor channel with high affinity for domoate and kainate. EMBO J 11(4):1651–1656
Werner P, Voigt M, Keinanen K, Wisden W, Seeburg PH (1991) Cloning of a putative high-affinity kainate receptor expressed pre- dominantly in hippocampal CA3 cells. Nature 351(6329):742–744
Hollmann M, Hartley M, Heinemann S (1991) Ca2+ permeability of KA-AMPA-- gated glutamate receptor channels depends on subunit composition. Science 252(5007):851–853
Hume RI, Dingledine R, Heinemann SF (1991) Identification of a site in glutamate receptor subunits that controls calcium permeability. Science 253(5023):1028–1031
Sommer B, Keinanen K, Verdoorn TA, Wisden W, Burnashev N, Herb A, Kohler M, Takagi T, Sakmann B, Seeburg PH (1990) Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS. Science 249(4976):1580–1585
Edmonds B, Gibb AJ, Colquhoun D (1995) Mechanisms of activation of glutamate receptors and the time course of excitatory synaptic currents. Annu Rev Physiol 57:495–519
Kiskin NI, Krishtal OA, Tsyndrenko A (1986) Excitatory amino acid receptors in hippocampal neurons: kainate fails to desensitize them. Neurosci Lett 63(3):225–230
Llano I, Marty A, Armstrong CM, Konnerth A (1991) Synaptic- and agonist-induced excitatory currents of Purkinje cells in rat cerebellar slices. J Physiol 434:183–213
Nelson PG, Pun RY, Westbrook GL (1986) Synaptic excitation in cultures of mouse spinal cord neurones: receptor pharmacology and behaviour of synaptic currents. J Physiol 372:169–190
Patneau DK, Mayer ML (1990) Structure- activity relationships for amino acid transmitter candidates acting at N-methyl-D-aspartate and quisqualate receptors. J Neurosci 10(7):2385–2399
Silver RA, Traynelis SF, Cull-Candy SG (1992) Rapid-time-course miniature and evoked excitatory currents at cerebellar synapses in situ. Nature 355(6356):163–166
Trussell LO, Fischbach GD (1989) Glutamate receptor desensitization and its role in synaptic transmission. Neuron 3(2):209–218
Colquhoun D, Jonas P, Sakmann B (1992) Action of brief pulses of glutamate on AMPA/kainate receptors in patches from different neurones of rat hippocampal slices. J Physiol 458:261–287
Hestrin S (1992) Activation and desensitization of glutamate-activated channels mediating fast excitatory synaptic currents in the visual cortex. Neuron 9(5):991–999
Hestrin S (1993) Different glutamate receptor channels mediate fast excitatory synaptic currents in inhibitory and excitatory cortical neurons. Neuron 11(6):1083–1091
Raman IM, Trussell LO (1992) The kinetics of the response to glutamate and kainate in neurons of the avian cochlear nucleus. Neuron 9(1):173–186
Tang CM, Shi QY, Katchman A, Lynch G (1991) Modulation of the time course of fast EPSCs and glutamate channel kinetics by aniracetam. Science 254(5029):288–290
Veruki ML, Morkve SH, Hartveit E (2003) Functional properties of spontaneous EPSCs and non-NMDA receptors in rod amacrine (AII) cells in the rat retina. J Physiol 549(Pt 3):759–774
Sasaki YF, Rothe T, Premkumar LS, Das S, Cui J, Talantova MV, Wong HK, Gong X, Chan SF, Zhang D, Nakanishi N, Sucher NJ, Lipton SA (2002) Characterization and comparison of the NR3A subunit of the NMDA receptor in recombinant systems and primary cortical neurons. J Neurophysiol 87(4):2052–2063
Kleckner NW, Dingledine R (1988) Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes. Science 241(4867):835–837
Schneggenburger R, Zhou Z, Konnerth A, Neher E (1993) Fractional contribution of calcium to the cation current through glutamate receptor channels. Neuron 11(1):133–143
Sah P, Hestrin S, Nicoll RA (1990) Properties of excitatory postsynaptic currents recorded in vitro from rat hippocampal interneurones. J Physiol 430:605–616
Jahr CE, Stevens CF (1990) Voltage dependence of NMDA-activated macroscopic conductances predicted by single-channel kinetics. J Neurosci 10(9):3178–3182
Hestrin S, Sah P, Nicoll RA (1990) Mechanisms generating the time course of dual component excitatory synaptic currents recorded in hippocampal slices. Neuron 5(3):247–253
Jahr CE (1992) High probability opening of NMDA receptor channels by L-glutamate. Science 255(5043):470–472
Lester RA, Clements JD, Westbrook GL, Jahr CE (1990) Channel kinetics determine the time course of NMDA receptor-mediated synaptic currents. Nature 346(6284):565–567
Charpantier E, Barneoud P, Moser P, Besnard F, Sgard F (1998) Nicotinic acetylcholine subunit mRNA expression in dopaminergic neurons of the rat substantia nigra and ventral tegmental area. Neuroreport 9(13):3097–3101
Cimino M, Marini P, Fornasari D, Cattabeni F, Clementi F (1992) Distribution of nicotinic receptors in cynomolgus monkey brain and ganglia: localization of alpha 3 subunit mRNA, alpha-bungarotoxin and nicotine binding sites. Neuroscience 51(1):77–86
Clarke PB, Schwartz RD, Paul SM, Pert CB, Pert A (1985) Nicotinic binding in rat brain: autoradiographic comparison of [3H]acetyl- choline, [3H]nicotine, and [125I]-alpha- bungarotoxin. J Neurosci 5(5):1307–1315
Seguela P, Wadiche J, Dineley-Miller K, Dani JA, Patrick JW (1993) Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium. J Neurosci 13(2):596–604
Wada E, Wada K, Boulter J, Deneris E, Heinemann S, Patrick J, Swanson LW (1989) Distribution of alpha 2, alpha 3, alpha 4, and beta 2 neuronal nicotinic receptor subunit mRNAs in the central nervous system: a hybridization histochemical study in the rat. J Comp Neurol 284(2):314–335
Mulle C, Vidal C, Benoit P, Changeux JP (1991) Existence of different subtypes of nicotinic acetylcholine receptors in the rat habenulo-interpeduncular system. J Neurosci 11(8):2588–2597
Kuba K, Tanaka E, Kumamoto E, Minota S (1989) Patch clamp experiments on nicotinic acetylcholine receptor-ion channels in bull- frog sympathetic ganglion cells. Pflugers Arch 414(2):105–112
Mathie A, Cull-Candy SG, Colquhoun D (1987) Single-channel and whole-cell cur- rents evoked by acetylcholine in dissociated sympathetic neurons of the rat. Proc R Soc Lond B Biol Sci 232(1267):239–248
Moss BL, Schuetze SM, Role LW (1989) Functional properties and developmental regulation of nicotinic acetylcholine receptors on embryonic chicken sympathetic neurons. Neuron 3(5):597–607
Sargent PB (1993) The diversity of neuronal nicotinic acetylcholine receptors. Annu Rev Neurosci 16:403–443
Schofield GG, Weight FF, Adler M (1985) Single acetylcholine channel currents in sympathetic neurons. Brain Res 342(1):200–203
Dani JA (2001) Overview of nicotinic receptors and their roles in the central nervous system. Biol Psychiatry 49(3):166–174
Quick MW, Lester RA (2002) Desensitization of neuronal nicotinic receptors. J Neurobiol 53(4):457–478
Castro NG, Albuquerque EX (1993) Brief- lifetime, fast-inactivating ion channels account for the alpha-bungarotoxin-sensitive nicotinic response in hippocampal neurons. Neurosci Lett 164(1–2):137–140
Albuquerque EX, Alkondon M, Pereira EF, Castro NG, Schrattenholz A, Barbosa CT, Bonfante-Cabarcas R, Aracava Y, Eisenberg HM, Maelicke A (1997) Properties of neuronal nicotinic acetylcholine receptors: pharmacological characterization and modulation of synaptic function. J Pharmacol Exp Ther 280(3):1117–1136
Alkondon M, Albuquerque EX (1993) Diversity of nicotinic acetylcholine receptors in rat hippocampal neurons. J Pharmacol Exp Ther 265(3):1455–1473
Castro NG, Albuquerque EX (1995) alpha- Bungarotoxin-sensitive hippocampal nicotinic receptor channel has a high calcium permeability. Biophys J 68(2):516–524
Papke RL (1993) The kinetic properties of neuronal nicotinic receptors: genetic basis of functional diversity. Prog Neurobiol 41(4):509–531
Maricq AV, Peterson AS, Brake AJ, Myers RM, Julius D (1991) Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. Science 254(5030):432–437
Eisele JL, Bertrand S, Galzi JL, Devillers-Thiery A, Changeux JP, Bertrand D (1993) Chimaeric nicotinic-serotonergic receptor combines distinct ligand binding and channel specificities. Nature 366(6454):479–483
Neijt HC, te Duits IJ, Vijverberg HP (1988) Pharmacological characterization of serotonin 5-HT3 receptor-mediated electrical response in cultured mouse neuroblastoma cells. Neuropharmacology 27(3):301–307
van Hooft JA, Vijverberg HP (1996) Selection of distinct conformational states of the 5-HT3 receptor by full and partial agonists. Br J Pharmacol 117(5):839–846
Yakel JL, Lagrutta A, Adelman JP, North RA (1993) Single amino acid substitution affects desensitization of the 5-hydroxytryptamine type 3 receptor expressed in Xenopus oocytes. Proc Natl Acad Sci U S A 90(11):5030–5033
Blandina P, Goldfarb J, Craddock-Royal B, Green JP (1989) Release of endogenous dopamine by stimulation of 5-hydroxytryptamine3 receptors in rat striatum. J Pharmacol Exp Ther 251(3):803–809
Lummis SC (2012) 5-HT(3) receptors. J Biol Chem 287(48):40239–40245
Miquel MC, Emerit MB, Nosjean A, Simon A, Rumajogee P, Brisorgueil MJ, Doucet E, Hamon M, Verge D (2002) Differential sub- cellular localization of the 5-HT3-As receptor subunit in the rat central nervous system. Eur J Neurosci 15(3):449–457
Thompson AJ, Lummis SC (2006) 5-HT3 receptors. Curr Pharm Des 12(28):3615–3630
Chameau P, van Hooft JA (2006) Serotonin 5-HT(3) receptors in the central nervous system. Cell Tissue Res 326(2):573–581
Thompson AJ, Lummis SC (2007) The 5-HT3 receptor as a therapeutic target. Expert Opin Ther Targets 11(4):527–540
Derkach V, Surprenant A, North RA (1989) 5-HT3 receptors are membrane ion channels. Nature 339(6227):706–709
Yang J (1990) Ion permeation through 5-hydroxytryptamine-gated channels in neuroblastoma N18 cells. J Gen Physiol 96(6):1177–1198
Virginio C, North RA, Surprenant A (1998) Calcium permeability and block at homomeric and heteromeric P2X2 and P2X3 receptors, and P2X receptors in rat nodose neurones. J Physiol 510(Pt 1):27–35
Nicke A, Baumert HG, Rettinger J, Eichele A, Lambrecht G, Mutschler E, Schmalzing G (1998) P2X1 and P2X3 receptors form stable trimers: a novel structural motif of ligand- gated ion channels. EMBO J 17(11):3016–3028
Stoop R, Thomas S, Rassendren F, Kawashima E, Buell G, Surprenant A, North RA (1999) Contribution of individual subunits to the multimeric P2X(2) receptor: estimates based on methanethiosulfonate block at T336C. Mol Pharmacol 56(5):973–981
Torres GE, Egan TM, Voigt MM (1999) Hetero-oligomeric assembly of P2X receptor subunits. Specificities exist with regard to possible partners. J Biol Chem 274(10):6653–6659
Burnstock G, Knight GE (2004) Cellular distribution and functions of P2 receptor sub- types in different systems. Int Rev Cytol 240:31–304
Collo G, Neidhart S, Kawashima E, Kosco-Vilbois M, North RA, Buell G (1997) Tissue distribution of the P2X7 receptor. Neuropharmacology 36(9):1277–1283
Collo G, North RA, Kawashima E, Merlo-Pich E, Neidhart S, Surprenant A, Buell G (1996) Cloning OF P2X5 and P2X6 receptors and the distribution and properties of an extended family of ATP-gated ion channels. J Neurosci 16(8):2495–2507
Khakh BS (2001) Molecular physiology of P2X receptors and ATP signalling at synapses. Nat Rev Neurosci 2(3):165–174
Khakh BS, North RA (2006) P2X receptors as cell-surface ATP sensors in health and dis- ease. Nature 442(7102):527–532
Rubio ME, Soto F (2001) Distinct localization of P2X receptors at excitatory postsynaptic specializations. J Neurosci 21(2):641–653
Edwards FA, Gibb AJ, Colquhoun D (1992) ATP receptor-mediated synaptic currents in the central nervous system. Nature 359(6391):144–147
Shigetomi E, Kato F (2004) Action potential- independent release of glutamate by Ca2+ entry through presynaptic P2X receptors elicits postsynaptic firing in the brainstem autonomic network. J Neurosci 24(12):3125–3135
North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82(4):1013–1067
Masin M, Kerschensteiner D, Dumke K, Rubio ME, Soto F (2006) Fe65 interacts with P2X2 subunits at excitatory synapses and modulates receptor function. J Biol Chem 281(7):4100–4108
Zhang M, Zhong H, Vollmer C, Nurse CA (2000) Co-release of ATP and ACh mediates hypoxic signalling at rat carotid body chemoreceptors. J Physiol 525(Pt 1):143–158
Jo YH, Role LW (2002) Coordinate release of ATP and GABA at in vitro synapses of lateral hypothalamic neurons. J Neurosci 22(12):4794–4804
Pankratov Y, Lalo U, Verkhratsky A, North RA (2007) Quantal release of ATP in mouse cortex. J Gen Physiol 129(3):257–265
Stuber GD, Hnasko TS, Britt JP, Edwards RH, Bonci A (2010) Dopaminergic terminals in the nucleus accumbens but not the dorsal striatum corelease glutamate. J Neurosci 30(24):8229–8233
Hirasawa H, Betensky RA, Raviola E (2012) Corelease of dopamine and GABA by a retinal dopaminergic neuron. J Neurosci 32(38):13281–13291
Finger TE, Danilova V, Barrows J, Bartel DL, Vigers AJ, Stone L, Hellekant G, Kinnamon SC (2005) ATP signaling is crucial for communication from taste buds to gustatory nerves. Science 310(5753):1495–1499
Olsen RW, Sieghart W (2008) International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update. Pharmacol Rev 60(3):243–260
Gonzalez-Burgos G, Lewis DA (2008) GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia. Schizophr Bull 34(5):944–961
Farrant M, Nusser Z (2005) Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci 6(3):215–229
Jones MV, Westbrook GL (1997) Shaping of IPSCs by endogenous calcineurin activity. J Neurosci 17(20):7626–7633
Jones MV, Westbrook GL (1995) Desensitized states prolong GABAA channel responses to brief agonist pulses. Neuron 15(1):181–191
Maconochie DJ, Zempel JM, Steinbach JH (1994) How quickly can GABAA receptors open? Neuron 12(1):61–71
Chen L, Wang H, Vicini S, Olsen RW (2000) The gamma-aminobutyric acid type A (GABAA) receptor-associated protein (GABARAP) pro- motes GABAA receptor clustering and modulates the channel kinetics. Proc Natl Acad Sci U S A 97(21):11557–11562
Overstreet LS, Jones MV, Westbrook GL (2000) Slow desensitization regulates the availability of synaptic GABA(A) receptors. J Neurosci 20(21):7914–7921
Tia S, Wang JF, Kotchabhakdi N, Vicini S (1996) Distinct deactivation and desensitization kinetics of recombinant GABAA receptors. Neuropharmacology 35(9–10):1375–1382
Verdoorn TA, Draguhn A, Ymer S, Seeburg PH, Sakmann B (1990) Functional properties of recombinant rat GABAA receptors depend upon subunit composition. Neuron 4(6):919–928
Grudzinska J, Schemm R, Haeger S, Nicke A, Schmalzing G, Betz H, Laube B (2005) The beta subunit determines the ligand binding properties of synaptic glycine receptors. Neuron 45(5):727–739
Katz B, Miledi R (1973) The binding of acetylcholine to receptors and its removal from the synaptic cleft. J Physiol 231(3):549–574
Laube B (2002) Potentiation of inhibitory glycinergic neurotransmission by Zn2+: a synergistic interplay between presynaptic P2X2 and postsynaptic glycine receptors. Eur J Neurosci 16(6):1025–1036
Takahashi T, Momiyama A, Hirai K, Hishinuma F, Akagi H (1992) Functional correlation of fetal and adult forms of glycine receptors with developmental changes in inhibitory synaptic receptor channels. Neuron 9(6):1155–1161
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Graziane, N., Dong, Y. (2022). Kinetics of Synaptic Current. In: Graziane, N., Dong, Y. (eds) Electrophysiological Analysis of Synaptic Transmission. Neuromethods, vol 187. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2589-7_17
Download citation
DOI: https://doi.org/10.1007/978-1-0716-2589-7_17
Published:
Publisher Name: Humana, New York, NY
Print ISBN: 978-1-0716-2588-0
Online ISBN: 978-1-0716-2589-7
eBook Packages: Springer Protocols