Location, location, location

Position is everything, at least in the world of cell signalling. Position of molecules has long been thought to explain how a globally applied signal produces specific effects in isolated populations of cells. For example, appropriately placed adrenoceptors on cells in the heart and hippocampus mediate the increase in heart rate and altered learning ability observed after a rush of adrenaline. But these G-protein-coupled receptors (GPCRs) work by activating downstream effectors, such as ion channels, by means of second messenger cascades that are common to many of the 1,000 or so different GPCRs that are littered over the surface of a cell. So how does adrenoceptor activation lead to the targeting of specific effector systems, giving a unique response pattern? Hell and colleagues show that, for some β₂-adrenoceptors at least, the answer seems to lie in the relative positioning of the receptors and their targets.

Using immunoprecipitation from extracts of rat hippocampal neurons, the authors found that fishing for β₂-adrenoceptors resulted in co-purification of the pore-forming domain of the L-type calcium channel (Ca_v1.2). Ca_v1.2 is a specific target of β₂-adrenoceptor activation, and the result from Hell et al. shows that the two molecules are tightly bound together in a macromolecular complex. Moreover, the purified complex contained not just the receptor and effector, but also many elements of the intermediate signalling cascade: the G-protein subunits, the adenylyl cyclase that catalyses the formation of cyclic AMP, the cAMP-dependent protein kinase that increases the activity of Ca_v1.2 by phosphorylation, and a phosphatase that removes this activating group. The β₂-adrenoceptor signalling complex, therefore, seems to be preassembled in these neurons, and ready for action.

But are such complexes necessary for effective signalling? The authors addressed this question by recording the activity of Ca_v1.2 channels in small segments of cultured hippocampal neurons during the application of the β₂-adrenoceptor agonist albuterol. Albuterol was able to activate the observed Ca_v1.2 channels only when delivered to the cell through the recording electrode, but not when applied from outside to the rest of the cell. It therefore seems that albuterol-mediated activation of cAMP-dependent signalling pathways is only sufficiently robust to open Ca_v1.2 channels that are directly associated with β₂-adrenoceptors as part of preassembled complexes.

Not all drugs that are specific for the same type of GPCR produce the same level of cellular activation, and this latest observation might help explain how certain agonists can produce smaller responses than others, even though they are acting through the same receptors. Unlike 'full agonists', which produce maximal responses, 'partial agonists' such as albuterol might activate the subset of effectors that are closely associated with their target receptors, but be unable to drive the activation of more distant, unassociated targets. What drives the assembly of these tightly bound complexes, and how different sorts of agonist might manage to produce different levels of activation of GPCR signalling cascades, are stories for another day.