Autoreceptors

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Autoreceptors (sometimes Autozeptoren ) are receptors of a nerve cell for their own neurotransmitters . They serve as part of a negative feedback loop within signal transduction . These receptors are found on the cell body ( soma or perikaryon ), on the dendrites and the terminal axon (the presynaptic endings ). The autoreceptors on cell bodies and dendrites are called soma-dendritic autoreceptors , those on the axon ends are called presynaptic autoreceptors .

Discovery story

The first indications of autoreceptors were pharmacological. It was observed that antagonists at neurotransmitter receptors not only weaken the postsynaptic nerve effects on the innervated cells, but also increase the presynaptic release of neurotransmitters from the axon ends. An important example of this is the sympathetic nervous system with its neurotransmitter norepinephrine . Norepinephrine causes the smooth muscles of blood vessels to contract. It acts on α- adrenoceptors . It has now been observed that α-adrenoceptor antagonists such as phenoxybenzamine not only weakened blood vessel contraction during sympathetic activity, but also increased the release of noradrenaline.

In 1971, many misinterpretations were followed by the fact that this increase is based on the blockade of presynaptic α-autoceptors, through which noradrenaline normally inhibits its own release. They became the prototypes of the α 2 adrenoceptors. In 1975 Arvid Carlsson coined the term “autoreceptor”. It appears that the overwhelming majority of nerve cells have such autoreceptors. It is predominantly G-protein-coupled receptors that usually mediate an inhibition of the nerve cell.

Presynaptic α 2A , α 2B or α 2C autoreceptor at an axon terminal with noradrenaline

species

Soma-dendritic autoreceptors

Soma-dendritic autoreceptors help regulate the creation of action potentials in the perikaryon. Another example are nerve cells with the neurotransmitter norepinephrine. They have soma-dendritic α 2 -autoreceptors. Via them, noradrenaline hyperpolarizes the cell membrane and thereby inhibits the development of action potentials. Another example are nerve cells with the neurotransmitter serotonin , which are mainly found in the brain. They have soma-dendritic 5-HT 1A autoreceptors through which serotonin inhibits the development of action potentials.

Presynaptic autoreceptors

They are one of the numerous presynaptic receptors . The picture shows the presynaptic α 2 -autoreceptors. Today we know three α 2 -adrenoceptors in humans, α 2A , α 2B and α 2C . All three can be built into the cell membrane of axon ends as autoreceptors with the transmitter noradrenaline, α 2A and α 2C being the more important. All three couple to heterotrimeric G proteins of the G i / o family. Their βγ subunit inhibits presynaptic calcium channels . When an action potential then occurs, less calcium flows into the axon ending and the release of norepinephrine decreases. A negative feedback results .

Analogously, nerve cells with the transmitter serotonin have presynaptic autoreceptors of the 5-HT 1B receptor type, nerve cells with the transmitter dopamine have presynaptic autoreceptors of the dopamine D 2 receptor type and nerve cells with acetylcholine presynaptic autoreceptors of the M 2 and M 4 type -Muscarine receptors . All of these receptors inhibit transmitter release. Nerve cells with the transmitter glutamic acid, on the other hand, have both release-inhibiting and release-increasing presynaptic autoreceptors.

Medical importance

The modulation of the activity of nerve cells by autoreceptors is part of their normal physiology. The fact that a malfunction of autoreceptors can lead to disease is best demonstrated for the α 2 -autoreceptors. Experimental animals that lack these autoreceptors release too much norepinephrine and are prone to high blood pressure and heart disease.

A reduction in the release of norepinephrine from the sympathetic system, on the other hand, contributes to the effect of the antihypertensive agent clonidine and related substances. Changes in autoreceptors are also part of the mechanism of action of psychotropic drugs .

Individual evidence

  1. ^ Stefan Silbernagl , Agamemnon Despopoulos : Taschenatlas Physiologie , 8th A, Thieme Verlag, 2012, ISBN 978-3-13-567708-8 , z. BS58 ; Register entry: "Auto (re) receptor".
  2. ↑ K. Starke : Presynaptic autoreceptors in the third decade: focus on α 2 -autoreceptors . In: Journal of Neurochemistry 2001; 78: 685-693
  3. ^ MR Bennett: One hundred years of adrenaline: the discovery of autoreceptors . In: Clinical Autonomic Research . 9, 1999, pp. 145-159. doi : 10.1007 / BF02281628 .
  4. ↑ Solomon Z. Langer: Presynaptic regulation of catecholamine release. In: Biochemical Pharmacology 1974; 23: 1793-1800
  5. ↑ a b Ralf Gilsbach and Lutz Hein: Presynaptic metabotropic receptors for acetylcholine and adrenaline / noradrenaline . In: Thomas C. Südhof and Klaus Starke : Pharmacology of Neurotransmitter Release. Handbook of Experimental Pharmacology 184, pp. 261-288, Springer, Berlin 2008. ISBN 978-3-540-74804-5
  6. ↑ Wolfgang Nörenberg, Ernst Schöffel, Bela Szabo and Klaus Starke: Subtype determination of soma-dendritic α 2 -autoreceptors in slices of rat locus coeruleus . In: Naunyn-Schmiedeberg's Archives of Pharmacology 1997; 356: 159-165
  7. ^ Lutz Hein, John D. Altman and Brian K. Kobilka: Two functionally distinct α 2 -adrenergic receptors regulate sympathetic neurotransmission. In: Nature (London) 1999; 402: 181-184
  8. ↑ M. Raiteri: Presynaptic metabotropic glutamate and GABA B receptors. In: Thomas C. Südhof and Klaus Starke: Pharmacology of Neurotransmitter Release. Handbook of Experimental Pharmacology 184, pp. 373-407, Springer, Berlin 2008. ISBN 978-3-540-74804-5
  9. ↑ Marc Brede, Frank Wiesmann, Roland Jahns, Kerstin Hadamek, Carsten Arnolt, Stefan Neubauer, Martin J. Lohse and Lutz Hein: Feedback inhibition of catecholamine release by two different α 2 -adrenoceptor subtypes prevents progression of heart failure. In: Circulation 2002; 106: 2491-2496
  10. ↑ a b Ralf Gilsbach, Johanna Schneider, Achim Lother, Stefanie Schickinger, Jost Leemhuis and Lutz Hein: Sympathetic α 2 -adrenoceptors prevent cardiac hypertrophy and fibrosis in mice at baseline but not after chronic pressure overload. In: Cardiovascular Research 2010; 86: 432-442
  11. ↑ K. Starke: Pharmacology of noradrenergic and adrenergic systems - pharmacotherapy of bronchial asthma - doping . In: K. Aktories, U. Förstermann, F. Hofmann and K. Starke (eds.): General and special pharmacology and toxicology , 10th edition, pp. 161–199, Urban & Fischer, Munich 2009, ISBN 978-3 -437-42522-6
  12. ↑ H. Bönisch, E. Schlicker, M. Göthert and W. Maier: Psychopharmaka - Pharmacotherapy of mental illnesses . In: K. Aktories, U. Förstermann, F. Hofmann and K. Starke (eds.): General and special pharmacology and toxicology , 10th edition, pp. 307–341, Urban & Fischer, Munich 2009, ISBN 978-3 -437-42522-6