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In attempting to elucidate the hitherto poorly understood action of the prostanoid-EP1 receptor, researchers in the US have uncovered a new type of receptor interaction and demonstrated its action on murine airway smooth muscle contraction.
Prostaglandin E2 (PGE2) produces its diverse biological effects by acting on four endogenous receptor subtypes (EP1–EP4). The authors set out to define the action of the EP1 receptor. In a series of experiments they first showed that activation of EP1 receptors by PGE2 failed to cause contraction of mouse tracheal ring, as might have been expected, but did cause a marked reduction in β2 adrenergic receptor (β2AR) mediated relaxation. This was shown to be mediated at the level of the receptor itself. This suggested an interplay between the EP1 receptor and the β2AR, with activation of the former resulting in decreased function of the latter. They went on to demonstrate coupling of the two receptors into a heterodimer. Activation of the EP1 receptor within the heterodimer causes a conformational change in the β2AR, uncoupling it from its G protein with resultant desensitisation to β2AR agonists.
This study demonstrates a novel modulatory function of the EP1 receptor in regulating the action of the β2AR. This may contribute to the reduced response to β2AR agonists in severe asthma, when there may be increased concentrations of endogenous PGE2.
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