Unifying Family A GPCR Theories of Activation

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Abstract

Several new pairs of active and inactive GPCR structures have recently been solved enabling detailed structural insight into the activation process, not only of rhodopsin but now also of the β2 adrenergic, M2 muscarinic and adenosine A2A receptors. Combined with structural analyses they have enabled us to examine the different recent theories proposed for GPCR activation and show that they are all indeed parts of the same process, and are intrinsically related through their effect on the central hydrophobic core of GPCRs. This new unifying general process of activation is consistent with the identification of known constitutively active mutants and an in-depth conservational analysis of significant residues implicated in the process.

Section snippets

Introduction: GPCR activation and the differing mechanisms

Human G protein-coupled receptors (GPCRs), with at least 800 unique members (Fredriksson et al., 2003), comprise the largest family of cell-surface receptors. They are ubiquitous biological control points of the cell. External signals are translated by this membrane protein family into readable stimuli resulting in precise cell behaviours. Cell growth and differentiation, cardiovascular function, metabolism, immune responses and neurotransmission are examples of physiological responses

GPCR activation: a common mechanism

It is perhaps unsurprising that TM3 and TM6 are at the heart of any common activation pathway as they are in direct contact with every other helix except TM1 (Venkatakrishnan et al., 2013). Thus GPCR activation, whether initiated by ligands binding to the extracellular loops or to the primordial major and minor binding pockets (Rosenkilde et al., 2010), must in some way affect helices 3 & 6 to impart the common movements (Dore et al., 2011) seen within the active and inactive pairs available to

Initiation of activation

There is significant evidence for movement of TM3 and TM6, and the role of the ionic lock and the hydrophobic hindering mechanism in the activation of GPCRs (Fig. 2A). What is of considerable interest is the apparently different initial sequence of events exhibited by the different receptors in initiating the TM movements seen in the activation process.

For the β2-AR the binding and H-bonding of the agonist between residues N7.39, D3.32, S5.42 and S5.46 causes the inward movement of TM5 and TM7 (

Conclusion

The examination of the inactive and active receptors to date shows that the initiation of activation occurs via different residues at the top of the receptor whilst the main processes of activation, in the movements of TM3 and TM6 relative to one another, are always seen. These common movements of activation for TM3 and TM6 are the movement of TM3 upwards along its axis and the rotation of TM6, and these are only possible if the hydrophobic core or HHM undergoes rearrangement. The movements of

Conflict of interest statement

The authors declare that there are no conflicts of interest.

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