Presynaptic receptors

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Presynaptic receptors are receptors on the presynaptic endings of nerve cells . Messenger substances that dock here modify the functions of the presynaptic endings, especially the release of neurotransmitters .

history

The chemical nature of information transfer in synapses was discovered by Otto Loewi in 1921 . Since then, it has long been assumed - often unspoken - that only the presynaptic neurotransmitter and the postsynaptic receptors on the innervated cells that recognize the neurotransmitter and initiate the postsynaptic cell response are required for this information transfer. The presynaptic endings should then release their transmitter when action potentials arrive without any further modulation, but depending on the frequency of the action potentials.

However, as early as 1924 there was an indication that presynaptic endings also have receptors. In the isolated hearts of rabbits, nicotine released noradrenaline , the transmitter of the postganglionic sympathetic neurons of the heart, apparently through a direct effect on the presynaptic endings. It became clear that the endings had nicotine receptors , one of the two large groups of receptors for the messenger substance acetylcholine . However, these receptors have no physiological function. Although acetylcholine occurs as a transmitter of the parasympathetic nervous system in the heart, the quantities released from the parasympathetic nervous system are too small to activate the presynaptic nicotine receptors.

The first discovery of a physiologically relevant presynaptic receptor was also made in experiments with isolated hearts from rabbits. Ruth Lindmar, Konrad Löffelholz and Erich Muscholl from the Pharmacological Institute of the University of Mainz observed that acetylcholine and other substances that act as agonists on the other large group of receptors for acetylcholine, the muscarinic receptors , in rabbits' hearts are caused by sympathetic nerve activity (i.e. by action potentials) inhibited the triggered release of noradrenaline, and that this inhibition could be canceled by antagonists at muscarinic receptors such as atropine . The presynaptic endings of the postganglionic sympathetic neurons of the heart therefore had, in addition to the release-promoting nicotine receptors, also release-inhibiting muscarinic receptors (picture). On top of that, in contrast to the former, the latter served a physiological function. Namely, they were also activated by the small amounts of acetylcholine released from the parasympathetic nervous system in the heart.

Presynaptic inhibition of norepinephrine release by muscarinic M 2 and M 4 receptors.

Presynaptic autoreceptors

Shortly after the presynaptic muscarinic receptors were discovered on postganglionic sympathetic neurons, it was discovered that many presynaptic endings also have receptors for their own transmitter. These presynaptic autoreceptors are used for negative feedback . Once a certain distribution density is reached, any further release is inhibited by transmitters that have already been released.

Presynaptic receptors on nerve cells with noradrenaline as a transmitter

They are the best known presynaptic receptors. Nerve cells with noradrenaline - called noradrenaline neurons for short - occur on the one hand in the brain, especially in the locus caeruleus , on the other hand in the body periphery, there as transmitters of the postganglionic sympathetic neurons. The table gives an overview. The first line contains the presynaptic α 2 - autoreceptors , on the noradrenaline release its own inhibits the seventh erstentdeckten the muscarinic receptors. In addition, the release of noradrenaline can be modulated by transmitters from neighboring synaptic endings such as acetylcholine, serotonin and endogenous opioids as well as by hormones such as adrenaline, ACTH and angiotensin II and by tissue hormones such as adenosine, bradykinin and prostaglandins. The multitude of non-autoreceptors is sometimes called presynaptic "heteroreceptors".

Messenger substance Presynaptic receptor Change in norepinephrine release
Norepinephrine , adrenaline α 2 - adrenoceptor (autoreceptor) ↓
adrenaline β 2 adrenoceptor ↑
Dopamine D 2 receptor ↓
histamine H 3 receptor ↓
Serotonin 5-HT 1 receptor ↓
Acetylcholine Nicotine receptor ↑
Acetylcholine Muscarinic M 2 and M 4 receptors ↓
γ-aminobutyric acid GABA B receptor ↓
Adenosine Adenosine A 1 receptor ↓
Adenosine Adenosine A 2A receptor ↑
Adenosine triphosphate P2Y 12 and other P2Y receptors ↓
Adenosine triphosphate P2X 2 ↑
Endogenous opioids Opioid μ, δ, κ receptor ↓
Nociceptin ORL 1 receptor (opioid receptor-like-1 receptor) ↓
Neuropeptide Y NPY 2 receptor ↓
Adrenocorticotropin Melanocortin MC 2 receptor ↑
Angiotensin II AT 1 receptor ↑
Bradykinin B 2 receptor ↑
Endogenous cannabinoids CB 1 receptor ↓
Prostaglandins Prostaglandin EP 3 receptor ↓

All of these presynaptic receptors primarily modulate the function of synapses. Some are also of general medical importance. The inhibition of the release of noradrenaline by the α 2 -Autoreceptors protects against cardiovascular diseases. The increase in the release of adrenaline via β 2 -adrenoceptors can contribute to the development of high blood pressure . The same goes for the increase in release from angiotensin. The inhibition of the release in the brain by opioids may be involved in their analgesic effects .

Presynaptic receptors on nerve cells with other transmitters

Almost all nerve cells have presynaptic receptors. The following four are among others physiologically and medically important.

Retrograde synaptic transmission through an endogenous cannabinoid
  • The sympathetic nervous system inhibits the peristalsis of the intestine. This is done in part by inhibiting the release of the parasympathetic transmitter acetylcholine. The noradrenalin of the sympathetic nervous system acts on presynaptic α 2 -adrenoceptors on the cholinergic neurons.
  • The dependency- generating effect of nicotine is based essentially on the release of dopamine from presynaptic endings in the nucleus accumbens . The nicotine receptors correspond to the nicotine receptors mentioned above on the endings of the postganglionic sympathetic neurons in the heart. The varenicline used to quit smoking attacks the presynaptic nicotine receptors in the nucleus accumbens.
  • In addition to the release of noradrenaline in the brain (table), opioids also inhibit the release of glutamic acid and substance P in the spinal cord via presynaptic receptors . Both are transmitters of pain-conducting neurons. This is a second component of the analgesic effects of opioids.
  • Most of the CB 1 receptors for Δ 9 -tetrahydrocannabinol and other cannabinoids are located on presynaptic endings (see also table). There they inhibit the release of transmitters and are primarily responsible for the many cannabinoid effects such as sedation , analgesia and ataxia . The picture shows a CB 1 receptor on a synaptic terminal with glutamic acid as the transmitter. It can not only be activated by plant ingredients such as Δ 9 -tetrahydrocannabinol (Δ 9 -THC), but also by endogenous cannabinoids such as 2-arachidonylglycerol (2-AG). The result is the retrograde synaptic transmission shown in the picture :

Released glutamic acid (Glu) activates the postsynaptic glutamate receptors NMDA-R, AMPA-R and mGluR1. This causes calcium to enter the cytoplasm of the postsynaptic neuron. Calcium activates the enzyme diacylglycerol lipase (DAGL), which catalyzes the formation of 2-AG. Finally, 2-AG acts on the presynaptic CB 1 receptor and inhibits the further release of glutamic acid. A role in learning and memory is ascribed to this retrograde synaptic transmission.

However, when looking for physiological and medical significance, the early skepticism should not be forgotten (from English): “The multitude of presynaptic receptors alone suggests that some are physiologically mute. ... They may be traces of evolution that persist because they do not harm us. "

Mechanisms of Presynaptic Modulation

The path from the arrival of an action potential in a presynaptic ending to the release of the transmitter through exocytosis is a multi-step process. An important step is an influx of calcium through presynaptic calcium channels. Where do the presynaptic receptors attack?

Some are messenger-activated ion channels. This subheading includes the nicotine receptors and the P2X receptors. Activated by the messenger substance, they open (increase their “open probability”), ions flow in or out, and the release changes.

Most presynaptic receptors, however, are G-protein-coupled receptors . This subheading includes the muscarinic receptors of the noradrenaline axon ending in the upper picture and the CB 1 receptors of the glutamic acid axon ending in the lower picture. They couple to G proteins of the G i / o family. The βγ subunit is then released from these, diffuses to neighboring calcium channels, reduces their probability of opening and thus inhibits exocytosis. This path is the most important of all. The presynaptic opioid receptors also use it.

But there are other mechanisms. The peptides angiotensin II and bradykinin increase the release of norepinephrine. Their receptors (see table) couple to the G protein G q . Its α-subunit increases the probability of neighboring calcium channels being open over several steps - the opposite of the effect of the βγ-subunit of G i / o .

Finally, there are receptor reaction cascades that open distal to the calcium influx, between the calcium influx and the exocytosis.

Individual evidence

  1. ^ O. Loewi: About humoral transmission of the cardiac nerve effect. In: Pflüger's archive. 193, 1921, pp. 201-213.
  2. ↑ Walter E. Dixon: Nicotine, Coniine, Piperidine, Lupetidine, Cytisine, Lobeline, Sparteine, Gelsemine. In: A. Heffter (Hrsg.): Handbuch der experimental Pharmakologie. Volume 2, Springer-Verlag, Berlin 1924, pp. 656-736.
  3. ↑ R. Lindmar, K.aken by spoon wood, E. Muscholl: A muscarinic mechanism inhibiting the release of noradrenaline from peripheral adrenergic nerve fibers by nicotinic agents. In: British Journal of Pharmacology . 32, 1968, pp. 280-294.
  4. ↑ K.öffelholz, E. Muscholl: Inhibition by parasympathetic nerve stimulation of the release of the adrenergic transmitter. In: Naunyn-Schmiedebergs Archive for Pharmacology . 267, 1970, pp. 181-184.
  5. ↑ Modified from Ralf Gilsbach, Lutz Hein: Presynaptic metabotropic receptors for acetylcholine and adrenaline / noradrenaline. In: Thomas C. Südhof , Klaus Starke (Ed.): Pharmacology of Neurotransmitter Release. (= Handbook of Experimental Pharmacology. 184). Springer-Verlag, Berlin 2008, ISBN 978-3-540-69246-1 , pp. 261-288.
  6. ↑ K. Starke: Regulation of noradrenaline release by presynaptic receptor systems. In: Reviews of Physiology, Biochemistry and Pharmacology . 77, 1977, pp. 1-124.
  7. ↑ Ralf Gilsbach, Johanna Schneider, Achim Lother, Stefanie Schickinger, Jost Leemhuis, Lutz Hein: Sympathetic α 2 -adrenoceptors prevent cardiac hypertrophy and fibrosis in mice at baseline but not after chronic pressure overload. In: Cardiovascular Research . 86, 2010, pp. 432-442.
  8. ^ SZ Langer, K. Starke, ML Dubocovich (Ed.): Presynaptic Receptors. Pergamon Press, Oxford 1979, ISBN 0-08-023190-X .
  9. ↑ Thomas V. Dunwiddie, David M. Lovinger (Eds.): Presynaptic Receptors in the Mammalian Brain. Birkhäuser, Boston 1993, ISBN 3-7643-3651-X .
  10. ↑ H. Fuder, E. Muscholl: Heteroreceptor-mediated modulation of noradrenaline and acetylcholine release from peripheral nerves. In: Reviews of Physiology, Biochemistry and Pharmacology. 126, 1995, pp. 265-412.
  11. ↑ Thomas C. Südhof, Klaus Starke (Ed.): Pharmacology of Neurotransmitter Release. (= Handbook of Experimental Pharmacology. 184). Springer-Verlag, Berlin 2008, ISBN 978-3-540-74804-5 .
  12. ↑ Modified from Bela Szabo: Function of the neuronal cannabinoid receptor. In: Biospectrum. in print
  13. ↑ Jacques Barik, Susan Wonnacott: Molecular and cellular mechanisms of action of nicotine in the CNS. In: Jack E. Henningfield, Edythe D. London, Sakire Pogun (eds.): Nicotine Psychopharmacology. (= Handbook of Experimental Pharmacology. 192). Springer-Verlag, Berlin 2009, ISBN 978-3-540-69246-1 , pp. 173-207.
  14. ↑ K. Starke: Presynaptic receptors. In: Annual Review of Pharmacology and Toxicology . 21, 1981, pp. 7-30.
  15. ↑ A. David Brown, Talvinder S. Sihra: Presynaptic signaling by heterotrimeric G-proteins. In: Thomas C. Südhof, Klaus Starke (Ed.): Pharmacology of Neurotransmitter Release. (= Handbook of Experimental Pharmacology. 184). Springer-Verlag, Berlin 2008, ISBN 978-3-540-69246-1 , pp. 207-260.