Abstract
Forty years ago, the introduction of a new electrophysiological technique, the patch clamp, revolutionized the fields of Cellular Physiology and Biophysics, providing for the first time the possibility of describing the behavior of a single protein, an ion-permeable channel of the cell plasma membrane, in its physiological environment. The new approach was actually much more potent and versatile than initially envisaged, and it has evolved into several different modalities that have radically changed our knowledge of how cells (not only the classical “electrically excitable “ones, such as nerves and muscles) use electrical signaling to modulate and organize their activity. This review aims at telling the history of the background from which the new technique evolved and at analyzing some of its more recent developments.
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Abbreviations
- ACh:
-
Acetylcholine
- HH:
-
Hodgkin and Huxley
- HTS:
-
High-throughput screening
- PC:
-
Patch clamp
- PCR:
-
Polymerase chain reaction
- Vm:
-
Membrane potential
References
Almers W, Stanfield PR, Stühmer W (1983) Lateral distribution of sodium and potassium channels in frog skeletal muscle: measurements with a patch clamp method. J Physiol 336:261–284
Böck J, Krogsaeter E, Passon M, Chao YK, Sharma S, Grallert H, Peters A, Grimm C (2021) Human genome diversity data reveal that L564P is the predominant TPC2 variant and a prerequisite for the blond hair associated M484L gain-of-function effect. PLoS Genet 17(1):e1009236
Brenowitz S, Duguid I, Kammermeier PJ (2017) Ion channels: history, diversity, and impact. Cold Spring Harb Protoc 7. https://doi.org/10.1101/pdb.top092288
Caccavano A, Bozzelli PL, Forcelli PA, Pak DTS, Wu JY, Conant K, Vicini S (2020) Inhibitory parvalbumin basket cell activity is selectively reduced during hippocampal sharp wave ripples in a mouse model of familial Alzheimer’s disease. J Neurosci 40:5116–5136
Carabelli V, Giancippoli A, Baldelli P, Carbone E, Artalejo AR (2003) Distinct potentiation of L-type currents and secretion by cAMP in rat chromaffin cells. Biophys J 85:1326–1337
Clarke SG, Scarnati MS, Paradiso KG (2016) Neurotransmitter release can be stabilized by a mechanism that prevents voltage changes near the end of action potentials from affecting calcium currents. J Neurosci 36:11559–11572
Colquhoun D (1991) Ion channels: this year’s Nobel prize in physiology or medicine. Opening channels of communication. Br Med J 303:938–939
Colquhoun D, Hawkes AG (1981) On the stochastic properties of single ion channels. Proc R Soc Lond B Biol Sci 211:205–235
Conti F, Neher E (1980) Single channel recordings of K+ currents in squid axons. Nature 285:140–143
Conti F, DeFelice LJ, Wanke E (1975) Potassium and sodium ion current noise in the membrane of the squid giant axon. J Physiol 248:45–82
Conti F, Hille B, Neumcke B, Nonner W, Stämpfli R (1976) Measurement of the conductance of the sodium channel from current fluctuations at the node of Ranvier. J Physiol 262:699–727
Damann N, Voets T, Nilius B (2008) TRPs in our senses. Curr Biol 18:R880–R889
Edwards FA, Konnerth A, Sakmann B, Takahashi T (1989) A thin slice preparation for patch clamp recordings from neurones of the mammalian central nervous system. Pflugers Arch 414:600–612
Espacenet (n.d.). https://worldwide.espacenet.com/advancedSearch?locale=en_ep
Ferraro M, Levi R, Lovisolo D, Vadacchino M (1983) Voltage noise in honeybee drone photoreceptors. Biophys Struct Mech 10:129–142
Gao M, Lim S, Chubykin AA (2021) Visual familiarity induced 5-Hz oscillations and improved orientation and direction selectivities in V1. J Neurosci 41:2656–2667
Gericke M, Droogmans G, Nilius B (1993) Thapsigargin discharges intracellular calcium stores and induces transmembrane currents in human endothelial cells. Pflugers Arch 422:552–557
Gray R, Johnston D (1985) Rectification of single GABA-gated chloride channels in adult hippocampal neurons. J Neurophysiol 54:134–142
Halliwell RF (2007) A short history of the rise of the molecular pharmacology of ionotropic drug receptors. Trends Pharmacol Sci 28:214–218
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch 391:85–100
Hartzell HC, Fischmeister R (1987) Effect of forskolin and acetylcholine on calcium current in single isolated cardiac myocytes. Mol Pharmacol 32:639–645
Hille B (1967) The selective inhibition of delayed potassium currents in nerve by tetraethylammonium ion. J Gen Physiol 50:1287–1302
Hille B (1970) Ionic channels in nerve membranes. Prog Biophys Mol Biol 21:3–30
Hille B (1984) Ionic channels of excitable membranes. Sinauer
Hille B (2018) The founding of journal of general physiology: membrane permeation and ion selectivity. J Gen Physiol 150:389–400
Hodgkin AL (1964) The conduction of the nervous impulse. Liverpool University Press
Hodgkin AL, Huxley AF (1952) Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. J Physiol 116:449–472
Holst GL, Stoy W, Yang B, Kolb I, Kodandaramaiah SB, Li L, Knoblich U, Zeng H, Haider B, Boyden ES, Forest CR (2019) Autonomous patch-clamp robot for functional characterization of neurons in vivo: development and application to mouse visual cortex. J Neurophysiol 121:2341–2357
Horn R, Marty A (1988) Muscarinic activation of ionic currents measured by a new whole-cell recording method. J Gen Physiol 92:145–159
Horn R, Patlak J (1980) Single channel currents from excised patches of muscle membrane. Proc Natl Acad Sci U S A 77:6930–6934
Hucho F, Changeux JP (1973) Molecular weight and quaternary structure of the cholinergic receptor protein extracted by detergents from Electrophorus electricus electric tissue. FEBS Lett 38:11–15
Huxley AF (2002) From overshoot to voltage clamp. Trends Neurosci 25:553–558
Jayant K, Wenzel M, Bando Y, Hamm JP, Mandriota N, Rabinowitz JH, Plante IJ, Owen JS, Sahin O, Shepard KL, Yuste R (2019) Flexible nanopipettes for minimally invasive intracellular electrophysiology in vivo. Cell Rep 26:266–278
Katz B (1966) Nerve, muscle, and synapse. McGraw-Hill
Katz B, Miledi R (1965) Propagation of electric activity in motor nerve terminals. Proc R Soc Lond Ser B Biol Sci 161:453–482
Katz B, Miledi R (1972) The statistical nature of the acetylcholine potential and its molecular components. J Physiol 224:665–699
Katz B, Miledi R (1979) Membrane noise produced by acetylcholine. Nature 226:962–963
Kodandaramaiah SB, Franzesi GT, Chow BY, Boyden ES, Forest CR (2012) Automated whole-cell patch-clamp electrophysiology of neurons in vivo. Nat Methods 9:585–587
Kodandaramaiah SB, Flores FJ, Holst GL, Singer AC, Han X, Brown EN, Boyden ES, Forest CR (2018) Multi-neuron intracellular recording in vivo via interacting autopatching robots. eLife 7:e24656
Kostyuk PG, Krishtal OA (1977) Effects of calcium and calcium-chelating agents on the inward and outward current in the membrane of mollusc neurones. J Physiol 270:569–580
Lamb TD, Simon EJ (1977) Analysis of electrical noise in turtle cones. J Physiol 272:435–468
Lambolez B, Audinat E, Bochet P, Crépel F, Rossier J (1992) AMPA receptor subunits expressed by single Purkinje cells. Neuron 9:247–258
Lassignal NL, Martin AR (1976) Reversal of acetylcholine potentials in eel electroplaque. Science 191:464–466
Lee AK, Manns ID, Sakmann B, Brecht M (2006) Whole-cell recordings in freely moving rats. Neuron 51:399–407
Lindau M, Neher E (1988) Patch-clamp techniques for time-resolved capacitance measurements in single cells. Pflugers Arch 411:137–146
Lombard J (2014) Once upon a time the cell membranes: 175 years of cell boundary research. Biol Direct 9:32
Luo Y, Shen W, Cline HT (2021) Electrophysiological recording for study of xenopus retinotectal circuitry. Cold Spring Harb Protoc. https://doi.org/10.1101/pdb.prot106880
Mak DO, Foskett JK (2015) Inositol 1,4,5-trisphosphate receptors in the endoplasmic reticulum: a single-channel point of view. Cell Calcium 58:67–78
Marty A, Finkelstein A (1975) Pores formed in lipid bilayer membranes by nystatin. Differences in its one-sided and two-sided action. J Gen Physiol 6:515–526
Minke B (2010) The history of the Drosophila TRP channel: the birth of a new channel superfamily. J Neurogenet 24:216–233
Minke B, Wu C, Pak WL (1975) Induction of photoreceptor voltage noise in the dark in Drosophila mutant. Nature 258:84–87
Moore JW, Naharashi T (1967) Tetrodotoxin’s highly selective blockage of an ionic channel. Fed Proc 26:1655–1663
Moore JW, Naharashi T, Shaw TI (1967) An upper limit to the number of sodium channels in nerve membrane? J Physiol 188:99–105
Mueller P, Rudin DO, Tien HT, Westcott WC (1962) Reconstitution of cell membrane structure in vitro and its transformation into an excitable system. Nature 194:979–980
Neher E, Lux HD (1969) Voltage clamp on Helix pomatia neuronal membrane; current measurement over a limited area of the soma surface. Pflugers Arch 311:272–277
Neher E, Lux HD (1971) Properties of somatic membrane patches of snail neurons under voltage clamp. Pflugers Arch 322:35–38
Neher E, Marty A (1982) Discrete changes of cell membrane capacitance observed under conditions of enhanced secretion in bovine adrenal chromaffin cells. Proc Natl Acad Sci U S A 79:6712–6716
Neher E, Sakmann B (1976) Single-channel currents recorded from membrane of denervated muscle fibers. Nature 260:799–802
Neher E, Stevens CF (1977) Conductance fluctuations and ionic pores in membranes. Annu Rev Biophys Bioeng 6:345–381
Neher E, Sakmann B, Steinbach JH (1978) The extracellular patch clamp: a method for resolving currents through individual open channels in biological membranes. Pflugers Arch 375:219–228
Neo Biosystems (n.d.). https://www.neobiosystems.com/PatchMAX100A.php
Neuromatic Devices (2021). https://neuromaticdevices.com/author/nd0913/
Nilius B (2003) Pflügers Archiv and the advent of modern electrophysiology. From the first action potential to patch clamp. Pflugers Arch 447:267–271
Noda M, Shimizu S, Tanabe T, Takai T, Kayano T, Ikeda T, Takahashi H, Nakayama H, Kanaoka H, Minamino N, Kangawa K et al (1984) Primary structure of electrophorus electricus sodium channel deduced from cDNA sequence. Nature 312:121–127
Obergrussberger A, Friis S, Brüggemann A, Fertig N (2021) Automated patch clamp in drug discovery: major breakthroughs and innovation in the last decade. Expert Opin Drug Discov 16:1–5
Reyes AD (2019) Neuronal signals thoroughly recorded. Nature 575:38–39
Rollenhagen A, Ohana O, Sätzler K, Hilgetag CC, Kuhl D, Lübke JHR (2018) Structural properties of synaptic transmission and temporal dynamics at excitatory layer 5B synapses in the adult rat somatosensory cortex. Front Synaptic Neurosci 10:24
Rosholm KR, Boddum K, Lindquist A (2021) Perforated whole-cell recordings in automated patch clamp electrophysiology. Methods Mol Biol 2188:93–108
Saiki RK, Scharf S, Faloona F, Mullis KB, Horn GT, Erlich HA, Arnheim N (1985) Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science 230:1350–1354
Sakmann B (2006) Patch pipettes are more useful than initially thought: simultaneous pre- and postsynaptic recording from mammalian CNS synapses in vitro and in vivo. Pflugers Arch 453:249–259
Sakmann B, Neher E (eds) (1983) Single-channel recording. Plenum Press
Santi MR, Vicini S, Eldadah B, Neale JH (1994) Analysis by polymerase chain reaction of alpha 1 and alpha 6 GABAA receptor subunit mRNAs in individual cerebellar neurons after whole-cell recordings. J Neurochem 63:2357–2360
Siegelbaum SA, Camardo JS, Kandel ER (1982) Serotonin and cyclic AMP close single K+ channels in Aplysia sensory neurones. Nature 299:413–417
Sigworth FJ (1986) The patch clamp is more useful than anyone had expected. Fed Proc 45:2673–2677
Sigworth FJ (2010) Molecular switches for “animal electricity”, Chapter 15. In: Garwin L, Lincoln T (eds) A century of nature. University of Chicago Press, Chicago, pp 217–223
Sigworth FJ, Neher E (1980) Single Na+ channel currents observed in cultured rat muscle cells. Nature 287:447–449
Singer SJ, Nicolson GL (1972) The fluid mosaic model of the structure of cell membranes. Science 175:720–731
Suchyna TM, Markin VS, Sachs F (2009) Biophysics and structure of the patch and the gigaseal. Biophys J 97:738–747
Sorgato MC, Keller BU, Stuhmer W (1987) Patch-clamping of the inner mitochondrial membrane reveals a voltage-dependent ion channel. Nature 330:498–500
Stevens CF (1972) Inferences about membrane properties from electrical noise measurements. Biophys J 12:1028–1047
Stevens CF (1977) Study of membrane permeability changes by fluctuation analysis. Nature 270:391–396
Sucher NJ, Deitcher DL (1995) PCR and patch-clamp analysis of single neurons. Neuron 14:1095–1100
Suk HJ, Boyden ES, van Welie I (2019) Advances in the automation of whole-cell patch clamp technology. J Neurosci Methods 326:108357
Suk HJ, Boyden ES, Van Welie I, Allen BD, Kodandaramaiah SB (2021) Image-guided closed-loop robotic system for automated whole-cell patch clamping electrophysiology of neurons in vivo. US Patent 10,993,634
Uta D, Oti T, Sakamoto T, Sakamoto H (2021) In vivo electrophysiology of peptidergic neurons in deep layers of the lumbar spinal cord after optogenetic stimulation of hypothalamic paraventricular oxytocin neurons in rats. Int J Mol Sci 22:3400
Verkhratsky A, Krishtal OA, Petersen OH (2006) From Galvani to patch clamp: the development of electrophysiology. Pflugers Arch 453:233–247
Verveen AA, Derksen HE, Schick KL (1967) Voltage fluctuations of neural membrane. Nature 216:588–589
Wagner CA, Friedrich B, Setiawan I, Lang F, Bröer S (2000) The use of Xenopus laevis oocytes for the functional characterization of heterologously expressed membrane proteins. Cell Physiol Biochem 10:1–12
Wanke E, DeFelice LJ, Conti F (1974) Voltage noise, current noise and impedance in space clamped squid giant axon. Pflugers Arch 347:63–74
Waters J, Larkum M, Sakmann B, Helmchen F (2003) Supralinear Ca2+ influx into dendritic tufts of layer 2/3 neocortical pyramidal neurons in vitro and in vivo. J Neurosci 23:8558–8867
Williams SR (2004) Spatial compartmentalization and functional impact of conductance in pyramidal neurons. Nat Neurosci 7:961–967
Williams SR, Atkinson SE (2008) Dendritic synaptic integration in central neurons. Curr Biol 18:R1045–R1047
Wilson DE, Scholl B, Fitzpatrick D (2018) Differential tuning of excitation and inhibition shapes direction selectivity in ferret visual cortex. Nature 560:97–101
Acknowledgements
I thank Drs. Alessandra Gilardino, Susanna Antoniotti, Chiara Ricca, and Stefano Zucca for technical support and advice. The interviews with Prof. Emilio Carbone and Prof. Stefano Vicini helped to reconstruct the atmosphere of the 1982 Erice School. A special thanks to Stefano Vicini for his invaluable, warm, and continued support and encouragement during the development of this project and to Prof. Giovanni Appendino and Prof. Bernd Nilius for their highly constructive criticism and suggestions, that helped to improve the text.
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Lovisolo, D. (2022). Patch Clamp: The First Four Decades of a Technique That Revolutionized Electrophysiology and Beyond. In: Pedersen, S.H.F. (eds) Reviews of Physiology, Biochemistry and Pharmacology. Reviews of Physiology, Biochemistry and Pharmacology, vol 186. Springer, Cham. https://doi.org/10.1007/112_2022_71
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