Low affinity analogs of thyrotropin-releasing hormone are super-agonists.
We show that several analogs of thyrotropin-releasing hormone (TRH) are more efficacious agonists at TRH receptors R1 and R2 than TRH itself. The apparent efficacies of the analogs were inversely related to their potencies and were independent of the nature of the modifications in TRH structure. In studies in intact cells, we showed that the differences in apparent efficacies were not due to differences in G-protein coupling, receptor desensitization, or recycling. Moreover, the differences in efficacies persisted in experiments using accessory protein-free membranes. We conclude that the efficacy differences of TRH analogs originated from the enhanced ability of TRH-R complexed to the low affinity agonists to directly activate G-protein(s), and not by a modulation of the activity of accessory proteins, and propose possible mechanisms for this phenomenon.
Clinical Endocrinology Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
Stanislav
S
Engel
Clinical Endocrinology Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
Susanne
S
Neumann
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar-160 062, Punjab, India.
Navneet
N
Kaur
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar-160 062, Punjab, India.
Vikramdeep
V
Monga
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar-160 062, Punjab, India.
Rahul
R
Jain
Laboratory of Cellular Biology, NIDCD, National Institutes of Health, Bethesda, Maryland 20892.
John
J
Northup
Clinical Endocrinology Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892. Electronic address: marving@intra.niddk.nih.gov.
Marvin C
MC
Gershengorn
D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D015394:Molecular Structure; D011485:Protein Binding; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000819:agonists*; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
D018025:Receptors, Thyrotropin-Releasing Hormone; D013973:Thyrotropin-Releasing Hormone; D019204:GTP-Binding Proteins