Physiological agonist-concentrations

18 June 2004

Kenneth L. Byron

In regard to Indu’s query: “What is really known about “physiological” concentrations of agonists?

In fact, the junctional architecture of the region where neurotransmitters are released near the plasma membrane of cells can in fact enable fairly high local concentrations of agonists. If receptors are strategically localized in this region, depending on the affinity and number of such receptors, one could elicit a “High” but extremely localized response. Any thoughts……?”

Neurotransmitter release, as well as other paracrine or autocrine signaling paradigms may very well produce quite high local concentrations of agonists and it’s important to consider whether these are the physiological mechanisms under which Ca2+ signals are being generated in the cells under investigation.

On the other hand, many of us investigate truly endocrine signaling phenomena where concentrations of agonists in the systemic circulation probably never approach the concentrations typically used to study store-operated Ca2+ entry pathways.

I think we ought to test a range of agonist concentrations that may reasonably cover the full range of concentrations expected physiologically in the system under investigation. Perhaps we should also focus more attention on trying to measure what concentrations are actually achieved in paracrine or autocrine signaling systems.

My guess is that store-operated channels are activated even at very low agonist concentrations, but the difficulty in detecting very low-level activity of these channels especially under physiological ionic conditions has prevented us from examining this in any detail.