Thymopoietin inhibits function and ligand binding to nicotinic receptors at the neuromuscular junction
Quik, M.; Collier, B.; Audhya, T.; Goldstein, G.
Journal of Pharmacology and Experimental Therapeutics 254(3): 1113-1119
1990
ISSN/ISBN: 0022-3565 PMID: 1967127 Document Number: 355229
Thymopoietin is a 48 to 49 amino acid polypepide hormone of the thymus, which regulates immune function. The present experiments show that the polypeptide can cause a complete block of transmission of the phrenic nerve diaphragm junction of the rat in vitro; contractile responses evoked by phrenic nerve stimulation were blocked by concentrations of thymopoietin as low as 10-8 M. The thymopoietin-induced inhibition of indirectly evoked muscle contractions were dose- and time-dependent, with the polypeptides being only slightly less potent than .alpha.-bungaro-toxin (.alpha.-BGT). Twitch responses to direct electrical stimulation of the muscles were not affected by thymopoietin, indicating that it did not inhibit muscle tension by an action on the muscle contractile mechanism per se. Furthermore, Thymopoietin did not alter resting or stimulated release of acetycholine from the phrenic nerve, suggesting that it did not interact at a presynaptic level. On the other hand, thymopoietin inhibited the binding of [125I].alpha.-BGT to thenicotinic receptor of the rat hemidiaphragm. In intact muscle tissue, the IC50 value for inhibition of [125I].alpha.-BGT binding by thymopoietin was 2.1 .times. 10-7 M, a value similr to the concentration of polypeptide required to inhibit phrenic nerve-induced muscle contraction (IC50 value, 0.75 -1.6 .times. 10-7 M). In a muscle membrane preparation the potency of thymopoietin to affect [125I].alpha.-BGT binding was increased (IC50 value, 0.35 nM); thus thymopoietin has the potential to interact at the nicotinic receptor in the nM range. To conclude, the present results show that thymopoietin inhibits neuromuscular activity by an effect that appears to be a specific interaction at the nicotinic receptor. These observations may have important implications for myasthenia gravis and/or other immune disorders associated with an impairment in neuromuscular transmission.