CILIARY NEUROTROPHIC FACTOR INDUCES DOWN-REGULATION OF ITS RECEPTOR AND DESENSITIZATION OF SIGNAL-TRANSDUCTION PATHWAYS IN-VIVO - NON-EQUIVALENCE WITH PHARMACOLOGICAL ACTIVITY

Despite the widespread use of polypeptide growth factors as pharmacolo gical agents, little is known about the extent to which these molecule s regulate their cognate cell surface receptors and signal transductio n pathways in vivo. We have addressed this issue with respect to the n eurotrophic molecule ciliary neurotrophic factor (CNTF). Administratio n of CNTF in vivo resulted in modest decreases in levels of CNTFR alph a mRNA and protein in skeletal muscle, CNTF causes the rapid tyrosine phosphorylation of LIFR beta and gp130 and the induction of the immedi ate-early gene, tis11; injection of CNTF 3-7 h after an initial exposu re failed to re-stimulate these immediate early responses, suggesting a biochemical desensitization to CNTF not accounted for by decreased r eceptor protein. To determine whether the desensitization of immediate -early responses caused by CNTF resulted in a functional desensitizati on, we compared the efficacy of multiple daily injections versus a sin gle daily dose of CNTF in preventing the denervation-induced atrophy o f skeletal muscle. Surprisingly, injections of CNTF every 6 h, which f alls within the putative refractory period for biochemical responses, resulted in efficacy equal to or greater than injections once daily. T hese results suggest that although much of the CNTF signal transductio n machinery is down-regulated with frequent CNTF dosing, biological si gnals continue to be recognized and interpreted by the cell.