Abstract
Hormones and neurotransmitters transduce signals through G protein-coupled
receptors (GPCR). Despite their common signaling pathways, however,
the responses they elicit have different temporal patterns. To reveal
the molecular basis for these differences we have developed a generally
applicable fluorescence-based technique for real-time monitoring
of the activation switch of GPCRs in living cells. We used such direct
measurements to investigate the activation of the alpha(2A)-adrenergic
receptor (alpha(2A)AR; neurotransmitter) and the parathyroid hormone
receptor (PTHR; hormone) and observed much faster kinetics than expected:
approximately 40 ms for the alpha(2A)AR and approximately 1 s for
the PTHR. The different switch times are in agreement with the different
receptors' biological functions. Agonists and antagonists could rapidly
switch the receptors on or off, whereas a partial agonist caused
only a partial signal. This approach allows the comparison of agonist
and partial agonist intrinsic activities at the receptor level and
provides evidence for millisecond activation times of GPCRs.
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