Vasoactive intestinal peptide receptor regulation and reversible desensitization in human colonic carcinoma cells in culture.

ABSTRACT

Vasoactive intestinal peptide (VIP) receptors are widely distributed in different tissues or carcinoma cells originating from entoderm and have been shown to regulate the growth of colonic adenocarcinoma cells through the action of cyclic AMP (cAMP). After exposure of cultured HT-29 human colonic carcinoma cells to 10(-8) M VIP, the cAMP-mediated signals in response to a new challenge with this neuropeptide were strongly attenuated as a function of time (half-life, less than 3 min) and VIP concentrations (half-maximal desensitization, 4 X 10(-9) M VIP). Desensitization is receptor mediated as indicated by (a) the pharmacological specificity of the desensitization (VIP greater than secretin); (b) the considerable decrease of the potentiative action of VIP on forskolin-induced cAMP generation; and (c) the close temporal relationship between VIP receptor desensitization and the disappearance of the VIP binding sites from the cell surface. Desensitization is reversible upon the removal of VIP. Recovery of functional VIP receptors is insensitive to cycloheximide treatment, is critically dependent upon temperature, and in optimal conditions (37 degrees C) does not exceed 75 and 55% of the binding of 125I-VIP monoiodinated on tyrosine residue and VIP-induced cAMP production, respectively. The characteristics of the desensitization and internalization/recycling of the VIP receptors in carcinoma cells in culture are consistent with the transient action of this neurotransmitter and underline the biological significance of these processes. The study of drugs and natural agents interfering with membrane regulation of VIP receptor density and activity may be of considerable importance in intestinal cell tumor biology.