How receptor mosaics decode transmitter signals. Possible relevance of cooperativity

doi:10.1016/j.tibs.2005.02.010

Trends in Biochemical Sciences

Volume 30, Issue 4, April 2005, Pages 188-193

https://doi.org/10.1016/j.tibs.2005.02.010 Get rights and content

It has been demonstrated that receptor–receptor interactions between G-protein-coupled receptors (GPCRs) occur at the plasma-membrane level. It has also been shown that clustering of GPCRs in aggregates or receptor mosaics (RMs) results in the reciprocal modulation of their binding and decoding characteristics. It is hypothesized that cooperativity plays an important part in the decoding of signals processed by RMs of GPCRs. Thus, the binding of the ligand at one receptor alters the likelihood of the same ligand binding at the next site, in the case of RMs, formed by identical receptors and/or by iso-receptors (receptors that bind the same ligand).

Section snippets

Models of signal transduction

Until recently, the current model of signal transduction maintained that the successive steps of the decoding process are organized in a ‘linear’ manner. In this model, the ligand interacts with the receptor and the ligand–receptor complex triggers specific signals in the cell (e.g. changes in the second-messenger levels) that cause multiple cellular chemical-physical responses. According to this view, the process starts to be divergent at the level of the second messenger. It was later

Allosteric control and cooperativity at the plasma-membrane level

In principle, it is possible to distinguish three types of RMs:

•
RM-type 1 (RM1). These are RMs formed by one type of receptor (homo-oligomers) or by iso-receptors (i.e. hetero-oligomers formed by different subtypes of the same receptor, such as dopamine D₁–D₂ and D₂–D₃ receptor hetero-oligomers 18, 19).
•
RM-type 2 (RM2). These are hetero-oligomers formed by different types of receptors. The same type or subtype of receptors can be present, but not in contact. Depending of which partner is

Allosteric interactions and cooperativity within a RM

Allosteric modulation can be thought of as one of the main biochemical mechanisms that enables transmission of information in horizontal molecular networks (HMNs; Box 2). Hence, communication among proteins forming a HMN can be envisaged as changes of conformations brought about by allosteric modulations caused, in some cases, by protein–protein interactions. In some instances, conformational changes can be induced by phosphorylation and dephosphorylation processes 13, 14, 15, 16, 27, 28. The

Potential types of cooperativity for intrasynaptic and extrasynaptic receptors

Lefkowitz and collaborators [32] obtained evidence for negative cooperativity among β-adrenergic receptors (for a discussion, see Ref. 33, 34) and found that negative cooperativity provides an exquisite sensitivity to low concentrations of ligands but protects the biological system against acute elevations of these ligands. It is our view that cooperativity in the case of the neurons could tune – in a subtle and differential manner – the strength of the synaptic versus the extra-synaptic

Concluding remarks

We postulate that, although negative cooperativity can be especially important for synaptic transmission, positive cooperativity can be essential for volume transmission. This represents a further functional value to the existence of RM.

These data and hypotheses on the ample spectrum of functional plasticity of GPCRs indicate the scope for future development of more selective drugs – in addition to those already available. It will also be important to consider the possibility that drugs can be

Acknowledgements

We dedicate this article to our young colleague Marco Celani, who sadly passed away. He had a promising future in Neuroscience.

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Trends in Biochemical Sciences

How receptor mosaics decode transmitter signals. Possible relevance of cooperativity

Section snippets

Models of signal transduction

Allosteric control and cooperativity at the plasma-membrane level

Allosteric interactions and cooperativity within a RM

Potential types of cooperativity for intrasynaptic and extrasynaptic receptors

Concluding remarks

Acknowledgements

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