Functional selectivity: Nature's Bach concerto

One of the great things about Bach’s organ music is how changes of a single note in a whole pattern can have rather dramatic effects on the sound. A unique and potentially very important similar phenomenon has been discovered recently in the area of GPCR research.

The understanding of the basic process by which GPCRs transmit signals from the cell exterior to the interior has seen remarkable advances in the last three decades, but much still remains to be deciphered. Our knowledge of signaling responses until now hinged on the action of agonists and antagonists. Central to this knowledge was the concept of ‘intrinsic efficacy’; according to this concept, there was no difference between two full agonists for instance, and both of them would produce the same response irrespective of the situation.

But this understanding failed to explain some observations. For instance, a full agonist would function as a partial agonist and even as an inverse agonist under different circumstances. Several such observations, especially in the context of GPCRs involved in neurotransmission, have forced a re-evaluation of the concept of intrinsic efficacy and led to an integrated formulation of a fascinating concept called ‘functional selectivity’.

So what is functional selectivity? It is the phenomenon by which the same kind of ligand (agonist, antagonist etc.) can modulate different signaling pathways activated by a single GPCR, leading to different physiological responses. Functional selectivity thus opens up a whole new method of modifying GPCR signaling in complex ways. It comprises a new layer of complexity and control that biological systems enforce at the molecular level to engage in complex signaling and homeostasis. Functional selectivity can allow the ‘tuning’ of ligands on a continuum scale of properties, from agonism to inverse agonism. In addition it can tightly regulate the strength of the particular property. It is what allows GPCRs to function as rheostats rather than as binary switches and allows them to exercise a fine layer of biological control and discrimination.

Functional selectivity is not just of academic interest. It can have clinical significance. Probably most tantalizingly, it may be one of the holy grails of pharmacology that allows us to separate the beneficial and harmful effects of a drug, leading to Paul Ehrlich’s ‘magic bullet’. Until now, side-effects have been predominantly thought to result from the lack of subtype-specificity of drugs. For instance, morphine’s side effects are thought to result from its activation of the μ-opioid receptor. But functional selectivity could provide a totally new avenue for explaining and possibly mitigating side-effects of drugs. For instance, consider the dopamine receptor agonist ropinirole, used in the treatment of Parkinson’s disease. There are several D-receptor agonists and just like them ropinirole interacts with several receptor subtypes. But unlike many of these, ropinirole does not demonstrate the dangerous side-effect named valvulopathy, a weakening of the heart valves that makes them stiff and inflamed. This can be a potentially life-threatening condition that seems to be facilitated by several dopamine agonists, but not ropinirole. The cause seems to be becoming clear only now; ropinirole is a functionally selective ligand that activates a certain pattern of second messenger pathways that is different from those activated by other agonists. Somehow this pattern of pathways is responsible for reduced valvulopathy.

Let’s go back to the organ/piano analogy to gauge the significance of such control. The sound produced by a piano depends on two variables- the exact identities of the keys pressed, and the intensity (how hard or softly you press them). The second variable can be as important as the first since a pressing a key particularly hard can drown out other notes and influence the very nature of the sound. The analogy to functional selectivity would be in looking at the keys themselves as different signaling pathways and the intensity of the notes as the strength of the pathways. Now, if one ligand binding to a single GPCR is able to activate a specific combination of these pathways, each with its own strengths, think of the permutations and combinations you could get from a set of even a dozen pathways- an astonishing number. Thus, functional selectivity could be the key that unlocks the puzzle of how one ligand can put into motion such a complex set of signaling events and physiological responses. One ligand- one receptor- several pathways with differing strengths. An added variable is the concentration of certain second messengers in a particular environment or cell type, which could add even more combinations. This picture could go a long way toward explaining how we can get such complex signaling in the brain from just a few ligands like dopamine, serotonin and histamine. And as described above, it also provides a fascinating direction - along with control of subtype selectivity (a much more well known and accepted cause) - for developing therapies that demonstrate all the good stuff without the bad stuff.

The basic foundation of functional selectivity is as tantalizing. Whatever the reasons for the phenomenon, the proximal cause for it has to concern the stabilization of different protein conformations by the same kind of ligands. Unravel these protein conformations and you would make significant inroads into unraveling functional selectivity. If you come to think of it, this principle is not too different from the current model of conformational selection used in explaining the action of agonists and antagonists in general, which involves the stabilization of certain conformations by specific molecules.

Nature never ceases to amaze. As we plumb its mysteries further, it reveals deeper, more subtle and finer layers of control and discrimination that allows it to generate profound complexity starting from some relatively simple events like the binding of a disarmingly simple molecule like adrenaline to a protein. And combined with the action of several proteins, the concerto turns into a symphony. We have been privileged to be in the audience.

Mailman, R., & Murthy, V. (2010). Ligand functional selectivity advances our understanding of drug mechanisms and drug discovery Neuropsychopharmacology, 35 (1), 345-346 DOI: 10.1038/npp.2009.117

Kelly, E., Bailey, C., & Henderson, G. (2009). Agonist-selective mechanisms of GPCR desensitization British Journal of Pharmacology, 153 (S1) DOI: 10.1038/sj.bjp.0707604