New cel­lu­lar nano­world discovered

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New cel­lu­lar nano­world discovered

A research team led by Martin Lohse has now shown how a cell can pro­cess hun­dreds of sig­nals sim­ul­tan­eously. The new res­ults, pub­lished in the pres­ti­gi­ous journal “Cell”, will open up a com­pletely new field of research in cell biology.

A liv­ing cell is exposed to a vari­ety of stim­uli. Count­less mes­sen­ger sub­stances, hor­mones and neur­o­trans­mit­ters, dock onto its sur­face, trans­mit their mes­sages and trig­ger sig­nals inside the cell. In response, the cell changes its func­tions, its meta­bol­ism or switches genes in the cell nuc­leus on or off. Recept­ors in the cell mem­brane receive the inform­a­tion for all these orders. The mes­sages from the out­side world are recog­nized by many dif­fer­ent recept­ors loc­ated in the cell mem­brane. But how does the cell man­age to dis­tin­guish between the sig­nals of dif­fer­ent recept­ors? A team led by ISAR chair­man Martin Lohse and includ­ing research­ers from the Max Del­brück Cen­ter in Ber­lin and the Uni­ver­sity of Würzburg has now demon­strated that a pre­vi­ously unknown nano­world plays a cru­cial role.

There are more than 800 dif­fer­ent recept­ors loc­ated on cell sur­faces. Up to a hun­dred dif­fer­ent receptor types can be loc­ated on a single cell, and these in turn respond to com­pletely dif­fer­ent hor­mones and neur­o­trans­mit­ters in the body. “Count­less sig­nals come from out­side, which are recog­nized very spe­cific­ally by recept­ors – but inside the cell there are only a hand­ful of molecules that respond to the activ­a­tion. Yet they per­form diverse and com­pletely dif­fer­ent tasks,” says Andreas Bock. A long-time col­lab­or­ator of Martin Lohse, he has become a pro­fessor at the Uni­ver­sity of Leipzig in early 2022 and is co-senior author of the study pub­lished in the renowned journal “Cell”.

Com­mu­nic­a­tion in nano­meter-sized spaces

Cyc­lic aden­osine mono­phos­phate (cAMP) is the most import­ant sig­nal­ing molecule in the cell. It is pro­duced when cer­tain recept­ors are stim­u­lated. For example, if heart muscle cells are stim­u­lated with adren­aline, their cAMP level increases and the heart con­tracts faster and more force­fully. If the same cells are stim­u­lated with prostaglandin, the same amount of cAMP is pro­duced, but sur­pris­ingly the heart muscle hardly reacts.

Using fluor­es­cence micro­scopy, the research­ers used isol­ated single cells to invest­ig­ate how cAMP sig­nals from two dif­fer­ent recept­ors are gen­er­ated and pro­cessed in par­al­lel in one cell. They real­ized that under nor­mal con­di­tions, the increase in cAMP levels is lim­ited to tiny domains dir­ectly at the activ­ated receptor with a radius between 30 and 60 nano­met­ers. “These are com­part­ment­al­ized spaces in which the cAMP con­cen­tra­tion is very high – it is in them that the dif­fer­ent effects of cAMP arise,” explains Andreas Bock “We assume that the high spe­cificity of receptor stim­uli arises via the nar­row loc­al­iz­a­tion of the nano­spaces. We have named these small spaces RAINs: Receptor-asso­ci­ated inde­pend­ent nanodomains.”

“The dis­cov­ery of nan­odo­mains increases the com­plex­ity of sig­nal­ing path­ways in the cell many times over what we pre­vi­ously thought,” said Dr. Char­lotte Kayser. Together with Drs. Selma Anton and Isa­bella Mai­el­laro, she is first author of the study. Sig­nals that ori­gin­ate at the receptor first remain on site and only influ­ence the enzymes in the imme­di­ate vicin­ity. Other areas in the cell are there­fore not addressed by the sig­nals. This means that indi­vidual sig­nal­ing path­ways can be switched on and off very locally.

For a long time, sci­ent­ists regarded the cytosol, the interior of the cell, as a large “swim­ming pool” in which cell com­pon­ents move freely. But there appear to be pre­vi­ously unknown struc­tures that organ­ize the cell interior around each receptor. “We can­not see the nan­odo­mains dir­ectly – they are too small even for the best light micro­scopes,” explains senior author Pro­fessor Martin Lohse, former dir­ector of the Max Del­brück Cen­ter and now chair­man of ISAR Bioscience.

Cells can pro­cess large num­bers of sig­nals in parallel

The cell does not appear to be a switch that is either “on” or “off”. It func­tions more like a chip in which many sig­nals are pro­cessed sim­ul­tan­eously in a very small area, Lohse says. “This is very import­ant for nerve cells, for example, which can pro­cess dif­fer­ent sig­nals at their exten­sions in this way. One site can be activ­ated, while another stays quiet and a third is inhibited.”

When the sci­ent­ists stim­u­lated a cell with small amounts of mes­sen­ger – hor­mone or neur­o­trans­mit­ter – the nan­odo­mains were eas­ily vis­ible. With stronger stim­u­la­tion, the sig­nal­ing molecules “spilled over” and the spaces began to merge. This may have med­ical applic­a­tions. “It may be pos­sible to pro­duce not only quant­it­at­ively but also qual­it­at­ively dif­fer­ent effects with sub­stances that stim­u­late recept­ors to dif­fer­ent degrees – I’m think­ing of opioids, for example. Depend­ing on whether the triggered cAMP sig­nals affect only indi­vidual regions of the cell or encom­pass the entire cell,” adds Martin Lohse.

“We have taken a first look at a pre­vi­ously unima­gined nano­world within cells,” says Lohse. “With research fund­ing from the European Research Coun­cil, we have been look­ing for a “quantum world” for cel­lu­lar sig­nals since 2008 – now we can say that it really exists.” The first step is to bet­ter under­stand the struc­ture and com­pon­ents of such nan­odo­mains. How­ever, ini­tial find­ings already show that they do not func­tion prop­erly in dis­eased cells, such as liver can­cer cells or in the dis­eased heart. This makes the cel­lu­lar nano­world inter­est­ing for medi­cine as well.

Anton SE, Kayser C, Mai­el­laro I, Nemec K, Möller J, Kosch­in­ski A, Zac­colo M, Anni­bale P, Fal­cke M, Lohse MJ, Bock A (2022) Receptor-asso­ci­ated inde­pend­ent cAMP nan­odo­mains medi­ate spa­ti­otem­poral spe­cificity of GPCR signaling.
Cell DOI: https://doi.org/10.1016/j.cell.2022.02.011.

Tiny nan­odo­mains for cell signaling. 
The image shows a sec­tion of a cell; at the top, two dif­fer­ent recept­ors are loc­ated on the cell sur­face as an example: on the left, a receptor for GLP‑1, a hor­mone whose func­tion is impaired in dia­betes; on the right, a receptor for the stress hor­mone adren­aline. Both recept­ors trig­ger the pro­duc­tion of the sig­nal molecule cAMP in the cell via vari­ous inter­me­di­ate steps – but each receptor does so in a tiny nan­odo­main of its own. In this way, a cell can inde­pend­ently pro­cess the sig­nals of many dif­fer­ent recept­ors sim­ul­tan­eously. (Image: Char­lotte Kayser, MDC Berlin)