Persistence of evolutionary memory: primordial six-transmembrane helical domain mu opiate receptors selectively linked to endogenous morphine signaling.
Biochemical, molecular and pharmacological evidence for two unique six-transmembrane helical (TMH) domain opiate receptors expressed from the micro opioid receptor (MOR) gene have been shown. Designated micro3 and micro4 receptors, both protein species are Class A rhodopsin-like members of the superfamily of G-protein coupled receptors but are selectively tailored to mediate the cellular regulatory effects of endogenous morphine and related morphinan alkaloids via stimulation of nitric oxide (NO) production and release. Both micro3 and micro4 receptors lack an amino acid sequence of approximately 90 amino acids that constitute the extracellular N-terminal and TMH1 domains and part of the first intracellular loop of the micro1 receptor, but retain the empirically defined ligand binding pocket distributed across conserved TMH2, TMH3, and TMH7 domains of the micro1 sequence. Additionally, the receptor proteins are terminated by unique intracellular C-terminal amino acid sequences that serve as putative coupling or docking domains required for constitutive NO synthase activation. Because the recognition profile of micro3 and micro4 receptors is restricted to rigid benzylisoquinoline alkaloids typified by morphine and its extended family of chemical congeners, it is hypothesized that conformational stabilization provided by interaction of extended extracellular N-terminal protein domains and the extracellular loops is required for binding of endogenous opioid peptides as well as synthetic flexible opiate alkaloids.
Neuroscience Research Institute, State University of New York, College at Old Westbury, Old Westbury, NY 11568-0210, USA.
Richard M
RM
Kream
Melinda
M
Sheehan
Patrick
P
Cadet
Kirk J
KJ
Mantione
Wei
W
Zhu
Federico
F
Casares
George B
GB
Stefano
D000595:Amino Acid Sequence; D000818:Animals; D004789:Enzyme Activation; D019143:Evolution, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D009020:Morphine / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
D017450:Receptors, Opioid, mu; D009020:Morphine; D019001:Nitric Oxide Synthase