Melanocortin receptors and delta-opioid receptor mediate opposite signalling actions of POMC-derived peptides in CATH.a cells.
The locus coeruleus is innervated by proopiomelanocortin (POMC)-derived peptide immunoreactive fibres. The biological effects of ( melanocyte-stimulating hormone (aMSH) and [-endorphin on second messengers (cAMP, inositol phosphates) and gene transcription were studied in the locus cceruleus-derived cell line CATH.a. RT-PCR analysis revealed the presence of four MSH receptor subtypes (1, 3, 4 and 5). Activation of these receptors by diacetyl alphaMSH stimulated cAMP accumulation in a dose-dependent manner (EC50: 4 x 10(-9) M). Diacetyl alphaMSH stimulated transcription from reporter genes driven by the c-fos or tyrosine hydroxylase promoter. This effect was abolished when protein kinase A was inactivated with a dominant inhibitory mutant. RT-PCR analyses revealed the presence of delta-, but not mu-and kappa-opioid receptor. Pharmacological analysis showed that beta-endorphin (EC50: 2.5 x 10(-8)M), but not N-acetyl beta-endorphin, antagonized the biological effect of diacetyl alphaMSH on cAMP production and gene transcription. Since N-acetylation regulates the biological activity of alphaMSH and beta-endorphin in an opposite manner, we propose a model where the rate of secretion dictated by the bioelectric activity of the presynaptic neuron modulates POMC-derived peptide maturation and the resulting biological signal sensed by the postsynaptic plate.
René
F
F
Laboratoire de Neurophysiologie Cellulaire et Intégrée, UMR CNRS 7519, Strasbourg, France.
Muller
A
A
Jover
E
E
Kieffer
B
B
Koch
B
B
Loeffler
J P
JP
D000107:Acetylation; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D008125:Locus Coeruleus / Q000166:cytology / Q000502:physiology*; D016015:Logistic Models; D011333:Pro-Opiomelanocortin / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D018043:Receptors, Corticotropin / Q000502:physiology*; D044101:Receptors, Melanocortin; D017465:Receptors, Opioid, delta / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D000521:alpha-MSH / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001615:beta-Endorphin / Q000494:pharmacology
D016760:Proto-Oncogene Proteins c-fos; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D017465:Receptors, Opioid, delta; D000521:alpha-MSH; D001615:beta-Endorphin; D011333:Pro-Opiomelanocortin; D017868:Cyclic AMP-Dependent Protein Kinases