Agonist Induced Constitutive Receptor Activation as a Novel Regulatory Mechanism

Abstract

We propose the hypothesis that certain G protein coupled receptors can become constitutively activated during agonist stimulation so that the receptor remains active even after the agonist is removed. This new paradigm of receptor regulation may account for some long term effects of neurotransmitters and hormones. We have tested the hypothesis that constitutive µ receptor activation represents a crucial step driving narcotic tolerance and dependence. Our results indeed support the conversion of µ to a constitutively acitve state, µ*, observed in neuroblastoma SK-N-SH and SH-SY5Y tissue culture, in U293 cells transfected with theµ receptor gene, and in vivo. Constitutive p activation may result from receptor phosphorylation to yield µ*, and further, in vivo studies indicate that formation of µ* could account for narcotic tolerance and dependence.