β2AR: old horse’s new tricks

It’s almost four years since the Nobel prize in chemistry went to Brian Kobilka and Robert Lefkowitz for their contribution in our understanding of G protein-coupled receptor (GPCR) signaling. They did their most exciting work by studying β2 adrenergic receptor (β2AR). Yet, despite the titanic efforts, the receptor still holds lots of secrets from us.

Recently two letters in Nature from Kobilka, Lefkowitz, Costa, and Sunahara labs have shed some more light on the receptor dynamics during interaction with G protein (or mimicking antibodies*). They found that pharmacologically very similar agonists and antagonists at the (sub)molecular level trigger quite different conformational changes in β2AR. Apparently, somehow these gyrations funnel down to common dynamics that recruit G proteins and β-arrestins.

A little earlier biophysicists from Brussels published a paper that described how the composition of the membranes influences β2AR signaling. And it’s pretty remarkable (but not completely unexpected) that phospholipid composition can shift the equilibrium between active and inactive forms of the receptor. So here is another allosteric level of complexity. And a possible rationale for tissue-specific differences of β2AR-mediated effects.

A year ago researchers from Lefkowitz lab visualized recruitment of another cytoplasmic messenger, β-arrestin, by a chimeric β2V2 receptor (β2AR with C-terminus from vasopressin V2 receptor). Then they noticed that theoretically the chimeric protein may bind both β-arrestin and G protein at the same time! This could explain how class B GPCRs (e.g., V2) can signal after being withdrawn from the cell surface. So in the recent Cell paper researchers used the same chimeric β2V2 construct to make β2AR (class A GPCR) more like class B GPCR and to make it signal from within endosomes after internalization, by recruiting both G protein and β arrestins. One can’t prove it better than by making pictures of the whole mega-complex with a microscope. So they did it. Interestingly, earlier von Zastrow lab showed that β2AR can by itself activate adenylate cyclase after being trapped in endosomes but in the latest Cell paper it didn’t show much of an effect.

Purified (T4L)β2V2R–Gs-Nb35–βarr1-Fab30 megaplexes in electron microscope (source).

All these interconnecting allosteric effects call for a global effort to understand how in the end they influence the cross-membrane signal transduction. One of the most prominent contributors in this area is Madan Babu’s system biology lab. In the recent paper they showed that conformational rearrangements in many different GPCRs indeed converge to common patterns that recruit G proteins. At first sight the conclusion looks like nothing new but their analytical framework per se might be the most important part of the paper. The authors break apart the receptors’ structures into networks of through-space atomic contacts (rather than through covalent bonds, which makes more chemical sense). Then they consider the transitions between active and inactive states as the rearrangements of these networks. Previously they used a similar analysis to identify order-disorder transition as a common pattern in activation of different G proteins.

Order-disorder transition of Gα subunit and H5 helix of GPCR (source)

All the smart tricks aside, even the spectrum of biological roles of β2AR is far from completely known. For instance, in a recent PNAS paper Gat et al. found a correlation between the receptor activity in astrocytes and consolidation of hippocampal long-term memory in mice. The two phenomena somehow linked via β2AR-dependent L-lactate release from astrocytes. Who knows what else these receptors do in our body?

It’s fascinating how our understanding of GPCR signaling has refined from abstract pharmacological concepts to dynamic conformational changes in membrane proteins that convey extracellular stimuli inside cells. Today we know that rather than binary ‘on-off’ switches the receptors can adopt multiple active, inactive and intermediate conformations. We know that there are multiple cytoplasmic messengers that trigger diversity of pathways upon agonist binding. The signaling is therefore highly context- and time-dependent, can occur on the surface of the cells or even after the receptor’s internalization. The question remains open though if system biologists’ efforts to generalize the biophysics-derived reductionist findings will eventually enable us to predict the pharmacological outcomes of atomic butterfly effects.

* Tired of antibodies? Here’s another study that succeeded to develop RNA aptamers capturing activity-specific conformations of β2AR.

Header image was taken from Wikipedia



Author: Slava Bernat

I did my PhD in medicinal chemistry/chemical biology of G protein-coupled receptors and then explored some chemical biology of non-coding RNA as a postdoc. Currently I'm working in a small biotech company in San-Francisco Bay area as a research chemist. I'm writing about science, which catches my attention in rss feed reader and some random thoughts or tutorials.

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