Editing Action potential (section)

==History==
[[Image:PurkinjeCell.jpg|thumb|left|Image of two [[Purkinje cell]]s (labeled as '''A''') drawn by [[Santiago Ramón y Cajal]] in 1899. Large trees of [[dendrite]]s feed into the [[soma (biology)|soma]], from which a single [[axon]] emerges and moves generally downwards with a few branch points. The smaller cells labeled '''B''' are [[granule cell]]s.|alt=Hand drawn figure of two Purkinje cells side by side with dendrites projecting upwards that look like tree branches and a few axons projected downwards that connect to a few granule cells at the bottom of the drawing.]]

The role of electricity in the nervous systems of animals was first observed in dissected [[frog]]s by [[Luigi Galvani]], who studied it from 1791 to 1797.<ref name="piccolino_1997" group=lower-alpha>{{cite journal | vauthors = Piccolino M | title = Luigi Galvani and animal electricity: two centuries after the foundation of electrophysiology | journal = Trends in Neurosciences | volume = 20 | issue = 10 | pages = 443–8 | date = October 1997 | pmid = 9347609 | doi = 10.1016/S0166-2236(97)01101-6 | s2cid = 23394494 }}</ref> Galvani's results inspired [[Alessandro Volta]] to develop the [[Voltaic pile]]—the earliest-known [[battery (electricity)|electric battery]]—with which he studied animal electricity (such as [[electric eel]]s) and the physiological responses to applied [[direct current|direct-current]] [[voltage]]s.<ref name="piccolino_2000" group=lower-alpha>{{cite journal | vauthors = Piccolino M | title = The bicentennial of the Voltaic battery (1800-2000): the artificial electric organ | journal = Trends in Neurosciences | volume = 23 | issue = 4 | pages = 147–51 | date = April 2000 | pmid = 10717671 | doi = 10.1016/S0166-2236(99)01544-1 | s2cid = 393323 }}</ref>

In the 19th century scientists studied the propagation of electrical signals in whole [[nerve]]s (i.e., bundles of [[neuron]]s) and demonstrated that nervous tissue was made up of [[cell (biology)|cells]], instead of an interconnected network of tubes (a ''reticulum'').{{sfnm|1a1=Brazier|1y=1961|2a1=McHenry|2a2=Garrison|2y=1969|3a1=Worden|3a2=Swazey|3a3=Adelman|3y=1975}} [[Carlo Matteucci]] followed up Galvani's studies and demonstrated that injured nerves and muscles in frogs could produce [[direct current]]. Matteucci's work inspired the German physiologist, [[Emil du Bois-Reymond]], who discovered in 1843 that stimulating these muscle and nerve preparations produced a notable diminution in their resting currents, making him the first researcher to identify the electrical nature of the action potential.<ref>{{Cite book|title=Emil du Bois-Reymond : neuroscience, self, and society in nineteenth-century Germany|last=Finkelstein | first = Gabriel Ward | name-list-style = vanc |isbn=9781461950325|location=Cambridge, Massachusetts|oclc=864592470|year = 2013}}</ref> The [[conduction velocity]] of action potentials was then measured in 1850 by du Bois-Reymond's friend, [[Hermann von Helmholtz]].<ref>[[Kathryn Olesko|Olesko, Kathryn M.]], and Frederic L. Holmes. "Experiment, Quantification and Discovery: Helmholtz's Early Physiological Researches, 1843-50". In ''Hermann von Helmholtz and the Foundations of Nineteenth Century Science'', ed. David Cahan, 50-108. Berkeley; Los Angeles; London: University of California, 1994.</ref> Progress in electrophysiology stagnated thereafter due to the limitations of chemical theory and experimental practice. To establish that nervous tissue is made up of discrete cells, the Spanish physician [[Santiago Ramón y Cajal]] and his students used a stain developed by [[Camillo Golgi]] to reveal the myriad shapes of neurons, which they rendered painstakingly. For their discoveries, Golgi and Ramón y Cajal were awarded the 1906 [[Nobel Prize in Physiology or Medicine|Nobel Prize in Physiology]].<ref name="Nobel_1906" group=lower-Greek>{{cite press release | url = http://nobelprize.org/medicine/laureates/1906/index.html | title = The Nobel Prize in Physiology or Medicine 1906 | publisher = The Royal Swedish Academy of Science | year = 1906 | access-date = 2010-02-21 | url-status = live | archive-url = https://web.archive.org/web/20081204190959/http://nobelprize.org/medicine/laureates/1906/index.html | archive-date = 4 December 2008 | df = dmy-all }}</ref> Their work resolved a long-standing controversy in the [[neuroanatomy]] of the 19th century; Golgi himself had argued for the network model of the nervous system.

[[Image:3b8e.png|thumb|right|[[Ribbon diagram]] of the sodium–potassium pump in its E2-Pi state. The estimated boundaries of the [[lipid bilayer]] are shown as blue (intracellular) and red (extracellular) planes.|alt=Cartoon diagram of the sodium–potassium pump drawn vertically imbedded in a schematic diagram of a lipid bilayer represented by two parallel horizontal lines. The portion of the protein that is imbedded in the lipid bilayer is composed largely of anti-parallel beta sheets. There is also a large intracellular domain of the protein with a mixed alpha-helix/beta-sheet structure.]]

The 20th century saw significant breakthroughs in electrophysiology. In 1902 and again in 1912, [[Julius Bernstein]] advanced the hypothesis that the action potential resulted from a change in the [[permeation|permeability]] of the axonal membrane to ions.<ref name="bernstein_1902_1912" group=lower-alpha>{{cite journal | vauthors = Bernstein J | year = 1902 | title = Untersuchungen zur Thermodynamik der bioelektrischen Ströme | journal = Pflügers Archiv für die gesamte Physiologie | volume = 92 | pages = 521–562 | doi = 10.1007/BF01790181 | issue = 10–12| s2cid = 33229139 | author-link = Julius Bernstein | url = https://zenodo.org/record/2192363 }}</ref>{{sfn|Bernstein|1912}} Bernstein's hypothesis was confirmed by [[Kenneth Stewart Cole|Ken Cole]] and Howard Curtis, who showed that membrane conductance increases during an action potential.<ref group=lower-alpha>{{cite journal | vauthors = Cole KS, Curtis HJ | title = Electric Impedance of the Squid Giant Axon During Activity | journal = The Journal of General Physiology | volume = 22 | issue = 5 | pages = 649–70 | date = May 1939 | pmid = 19873125 | pmc = 2142006 | doi = 10.1085/jgp.22.5.649 | author-link1 = Kenneth Stewart Cole }}</ref> In 1907, [[Louis Lapicque]] suggested that the action potential was generated as a threshold was crossed,<ref group=lower-alpha>{{cite journal | vauthors = Lapicque L | year = 1907 | title = Recherches quantitatives sur l'excitationelectrique des nerfs traitee comme une polarisation | journal = J. Physiol. Pathol. Gen | volume = 9| pages = 620–635 }}</ref> what would be later shown as a product of the [[dynamical system]]s of ionic conductances. In 1949, [[Alan Lloyd Hodgkin|Alan Hodgkin]] and [[Bernard Katz]] refined Bernstein's hypothesis by considering that the axonal membrane might have different permeabilities to different ions; in particular, they demonstrated the crucial role of the sodium permeability for the action potential.<ref name="hodgkin_1949" group=lower-alpha>{{cite journal | vauthors = Hodgkin AL, Katz B | title = The effect of sodium ions on the electrical activity of giant axon of the squid | journal = The Journal of Physiology | volume = 108 | issue = 1 | pages = 37–77 | date = March 1949 | pmid = 18128147 | pmc = 1392331 | doi = 10.1113/jphysiol.1949.sp004310 | author-link1 = Alan Lloyd Hodgkin | author-link2 = Bernard Katz }}</ref> They made the first actual recording of the electrical changes across the neuronal membrane that mediate the action potential.<ref group=lower-Greek>{{cite journal |last=Warlow|first=Charles| name-list-style = vanc |title=The Recent Evolution of a Symbiotic Ion Channel in the Legume Family Altered Ion Conductance and Improved Functionality in Calcium Signaling|journal=Practical Neurology|volume=7|issue=3|pages=192–197|url=http://pn.bmj.com/content/7/3/192.full|publisher=BMJ Publishing Group|access-date=23 March 2013|url-status=live|archive-url=https://web.archive.org/web/20120314104408/http://pn.bmj.com/content/7/3/192.full|archive-date=14 March 2012|df=dmy-all|date=June 2007}}</ref> This line of research culminated in the five 1952 papers of Hodgkin, Katz and [[Andrew Huxley]], in which they applied the [[voltage clamp]] technique to determine the dependence of the axonal membrane's permeabilities to sodium and potassium ions on voltage and time, from which they were able to reconstruct the action potential quantitatively.<ref name="hodgkin_1952" group=lower-alpha>{{cite journal | vauthors = Hodgkin AL, Huxley AF, Katz B | title = Measurement of current-voltage relations in the membrane of the giant axon of Loligo | journal = The Journal of Physiology | volume = 116 | issue = 4 | pages = 424–48 | date = April 1952 | pmid = 14946712 | pmc = 1392219 | doi = 10.1113/jphysiol.1952.sp004716 | author-link1 = Alan Lloyd Hodgkin | author-link3 = Bernard Katz }}<br />* {{cite journal | vauthors = Hodgkin AL, Huxley AF | title = Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo | journal = The Journal of Physiology | volume = 116 | issue = 4 | pages = 449–72 | date = April 1952 | pmid = 14946713 | pmc = 1392213 | doi = 10.1113/jphysiol.1952.sp004717 | author-link1 = Alan Lloyd Hodgkin }}<br />* {{cite journal | vauthors = Hodgkin AL, Huxley AF | title = The components of membrane conductance in the giant axon of Loligo | journal = The Journal of Physiology | volume = 116 | issue = 4 | pages = 473–96 | date = April 1952 | pmid = 14946714 | pmc = 1392209 | doi = 10.1113/jphysiol.1952.sp004718 | author-link1 = Alan Lloyd Hodgkin }}<br />* {{cite journal | vauthors = Hodgkin AL, Huxley AF | title = The dual effect of membrane potential on sodium conductance in the giant axon of Loligo | journal = The Journal of Physiology | volume = 116 | issue = 4 | pages = 497–506 | date = April 1952 | pmid = 14946715 | pmc = 1392212 | doi = 10.1113/jphysiol.1952.sp004719 | author-link1 = Alan Lloyd Hodgkin }}<br />* {{cite journal | vauthors = Hodgkin AL, Huxley AF | title = A quantitative description of membrane current and its application to conduction and excitation in nerve | journal = The Journal of Physiology | volume = 117 | issue = 4 | pages = 500–44 | date = August 1952 | pmid = 12991237 | pmc = 1392413 | doi = 10.1113/jphysiol.1952.sp004764 | author-link1 = Alan Lloyd Hodgkin }}</ref> Hodgkin and Huxley correlated the properties of their mathematical model with discrete [[ion channel]]s that could exist in several different states, including "open", "closed", and "inactivated". Their hypotheses were confirmed in the mid-1970s and 1980s by [[Erwin Neher]] and [[Bert Sakmann]], who developed the technique of [[patch clamp]]ing to examine the conductance states of individual ion channels.<ref name="patch_clamp" group=lower-alpha>{{cite journal | vauthors = Neher E, Sakmann B | title = Single-channel currents recorded from membrane of denervated frog muscle fibres | journal = Nature | volume = 260 | issue = 5554 | pages = 799–802 | date = April 1976 | pmid = 1083489 | doi = 10.1038/260799a0 | author-link1 = Erwin Neher | bibcode = 1976Natur.260..799N | s2cid = 4204985 }}<br />* {{cite journal | vauthors = Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ | title = Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches | journal = Pflügers Archiv | volume = 391 | issue = 2 | pages = 85–100 | date = August 1981 | pmid = 6270629 | doi = 10.1007/BF00656997 | s2cid = 12014433 }}<br />* {{cite journal | vauthors = Neher E, Sakmann B | title = The patch clamp technique | journal = Scientific American | volume = 266 | issue = 3 | pages = 44–51 | date = March 1992 | pmid = 1374932 | doi = 10.1038/scientificamerican0392-44 | author-link1 = Erwin Neher | bibcode = 1992SciAm.266c..44N }}</ref> In the 21st century, researchers are beginning to understand the structural basis for these conductance states and for the selectivity of channels for their species of ion,<ref name="yellen_2002" group=lower-alpha>{{cite journal | vauthors = Yellen G | title = The voltage-gated potassium channels and their relatives | journal = Nature | volume = 419 | issue = 6902 | pages = 35–42 | date = September 2002 | pmid = 12214225 | doi = 10.1038/nature00978 | bibcode = 2002Natur.419...35Y | s2cid = 4420877 }}</ref> through the atomic-resolution [[X-ray crystallography|crystal structures]],<ref name="doyle_1998" group=lower-alpha>{{cite journal | vauthors = Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R | display-authors = 6 | title = The structure of the potassium channel: molecular basis of K+ conduction and selectivity | journal = Science | volume = 280 | issue = 5360 | pages = 69–77 | date = April 1998 | pmid = 9525859 | doi = 10.1126/science.280.5360.69 | bibcode = 1998Sci...280...69D }}<br />* {{cite journal | vauthors = Zhou Y, Morais-Cabral JH, Kaufman A, MacKinnon R | title = Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 A resolution | journal = Nature | volume = 414 | issue = 6859 | pages = 43–8 | date = November 2001 | pmid = 11689936 | doi = 10.1038/35102009 | bibcode = 2001Natur.414...43Z | s2cid = 205022645 }}<br />* {{cite journal | vauthors = Jiang Y, Lee A, Chen J, Ruta V, Cadene M, Chait BT, MacKinnon R | title = X-ray structure of a voltage-dependent K+ channel | journal = Nature | volume = 423 | issue = 6935 | pages = 33–41 | date = May 2003 | pmid = 12721618 | doi = 10.1038/nature01580 | bibcode = 2003Natur.423...33J | s2cid = 4347957 }}</ref> fluorescence distance measurements<ref name="FRET" group=lower-alpha >{{cite journal |author3-link=Paul R. Selvin | vauthors = Cha A, Snyder GE, Selvin PR, Bezanilla F | title = Atomic scale movement of the voltage-sensing region in a potassium channel measured via spectroscopy | journal = Nature | volume = 402 | issue = 6763 | pages = 809–13 | date = December 1999 | pmid = 10617201 | doi = 10.1038/45552 | bibcode = 1999Natur.402..809C | s2cid = 4353978 | doi-access = free }}<br />* {{cite journal | vauthors = Glauner KS, Mannuzzu LM, Gandhi CS, Isacoff EY | title = Spectroscopic mapping of voltage sensor movement in the Shaker potassium channel | journal = Nature | volume = 402 | issue = 6763 | pages = 813–7 | date = December 1999 | pmid = 10617202 | doi = 10.1038/45561 | bibcode = 1999Natur.402..813G | s2cid = 4417476 }}<br />* {{cite journal | vauthors = Bezanilla F | title = The voltage sensor in voltage-dependent ion channels | journal = Physiological Reviews | volume = 80 | issue = 2 | pages = 555–92 | date = April 2000 | pmid = 10747201 | doi = 10.1152/physrev.2000.80.2.555 | s2cid = 18629998 }}</ref> and [[cryo-electron microscopy]] studies.<ref name="cryoEM" group=lower-alpha>{{cite journal | vauthors = Catterall WA | title = A 3D view of sodium channels | journal = Nature | volume = 409 | issue = 6823 | pages = 988–9, 991 | date = February 2001 | pmid = 11234048 | doi = 10.1038/35059188 | bibcode = 2001Natur.409..988C | s2cid = 4371677 | doi-access = free }}<br />* {{cite journal | vauthors = Sato C, Ueno Y, Asai K, Takahashi K, Sato M, Engel A, Fujiyoshi Y | title = The voltage-sensitive sodium channel is a bell-shaped molecule with several cavities | journal = Nature | volume = 409 | issue = 6823 | pages = 1047–51 | date = February 2001 | pmid = 11234014 | doi = 10.1038/35059098 | bibcode = 2001Natur.409.1047S | s2cid = 4430165 }}</ref>

Julius Bernstein was also the first to introduce the [[Nernst equation]] for [[resting potential]] across the membrane; this was generalized by [[David E. Goldman]] to the eponymous [[Goldman equation]] in 1943.<ref name="goldman_1943" group=lower-alpha>{{cite journal | vauthors = Goldman DE | title = Potential, Impedance, and Rectification in Membranes | journal = The Journal of General Physiology | volume = 27 | issue = 1 | pages = 37–60 | date = September 1943 | pmid = 19873371 | pmc = 2142582 | doi = 10.1085/jgp.27.1.37 }}</ref> The [[sodium–potassium pump]] was identified in 1957<ref group=lower-alpha>{{cite journal | vauthors = Skou JC | title = The influence of some cations on an adenosine triphosphatase from peripheral nerves | journal = Biochimica et Biophysica Acta | volume = 23 | issue = 2 | pages = 394–401 | date = February 1957 | pmid = 13412736 | doi = 10.1016/0006-3002(57)90343-8 | s2cid = 32516710 }}</ref><ref group=lower-Greek>{{cite press release | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1997/press.html | title = The Nobel Prize in Chemistry 1997 | publisher = The Royal Swedish Academy of Science | year = 1997 | access-date = 2010-02-21 | url-status = live | archive-url = https://web.archive.org/web/20091023003257/http://nobelprize.org/nobel_prizes/medicine/laureates/1997/press.html | archive-date = 23 October 2009 | df = dmy-all }}</ref> and its properties gradually elucidated,<ref name="hodgkin_1955" group=lower-alpha>{{cite journal | vauthors = Hodgkin AL, Keynes RD | title = Active transport of cations in giant axons from Sepia and Loligo | journal = The Journal of Physiology | volume = 128 | issue = 1 | pages = 28–60 | date = April 1955 | pmid = 14368574 | pmc = 1365754 | doi = 10.1113/jphysiol.1955.sp005290 | author-link1 = Alan Lloyd Hodgkin }}</ref><ref name="caldwell_1960" group=lower-alpha>{{cite journal | vauthors = Caldwell PC, Hodgkin AL, Keynes RD, Shaw TL | title = The effects of injecting 'energy-rich' phosphate compounds on the active transport of ions in the giant axons of Loligo | journal = The Journal of Physiology | volume = 152 | issue = 3 | pages = 561–90 | date = July 1960 | pmid = 13806926 | pmc = 1363339 | doi = 10.1113/jphysiol.1960.sp006509 }}</ref><ref name="caldwell_1957" group=lower-alpha>{{cite journal | vauthors = Caldwell PC, Keynes RD | title = The utilization of phosphate bond energy for sodium extrusion from giant axons | journal = The Journal of Physiology | volume = 137 | issue = 1 | pages = 12–3P | date = June 1957 | pmid = 13439598 | doi = 10.1113/jphysiol.1957.sp005830 | s2cid = 222188054 }}</ref> culminating in the determination of its atomic-resolution structure by [[X-ray crystallography]].<ref name="Na_K_pump_structure" group=lower-alpha>{{cite journal | vauthors = Morth JP, Pedersen BP, Toustrup-Jensen MS, Sørensen TL, Petersen J, Andersen JP, Vilsen B, Nissen P | display-authors = 6 | title = Crystal structure of the sodium-potassium pump | journal = Nature | volume = 450 | issue = 7172 | pages = 1043–9 | date = December 2007 | pmid = 18075585 | doi = 10.1038/nature06419 | bibcode = 2007Natur.450.1043M | s2cid = 4344526 }}</ref> The crystal structures of related ionic pumps have also been solved, giving a broader view of how these [[molecular machine]]s work.<ref group=lower-alpha>{{cite journal | vauthors = Lee AG, East JM | title = What the structure of a calcium pump tells us about its mechanism | journal = The Biochemical Journal | volume = 356 | issue = Pt 3 | pages = 665–83 | date = June 2001 | pmid = 11389676 | pmc = 1221895 | doi = 10.1042/0264-6021:3560665 }}</ref>