Nelson's syndrome associated with a somatic frame shift mutation in the glucocorticoid receptor gene.

Nelson's syndrome is the appearance and/or progression of ACTH-secreting pituitary macroadenomas in patients who had previously undergone bilateral adrenalectomy for Cushing's disease. Extremely high plasma ACTH levels and aggressive neoplastic growth might be explained by the lack of appropriate glucocorticoid negative feedback due to defective glucocorticoid signal transduction. To study the glucocorticoid receptor (GR) gene in Nelson's syndrome, DNA was extracted from pituitary adenomas and leukocytes of four patients with this condition and amplified by PCR for direct sequence analysis. In one of the tumors, a heterozygous mutation, consisting of an insertion of a thymine between complementary DNA nucleotides 1188 and 1189, was found in exon 2. This frame-shift mutation led to premature termination at amino acid residue 366 of the wild-type coding sequence, excluding the expression of a functioning receptor protein from the defective allele. The mutation was not detected in the sequence of the GR gene in the patient's leukocyte DNA, indicating a somatic origin. By lowering the receptor number in tumorous cells, this defect might have caused local resistance to negative glucocorticoid feedback similar to that caused by the presence of a null allele in a kindred with the generalized glucocorticoid resistance syndrome. P53 protein accumulation, previously reported in 60% of corticotropinomas, could not be detected in any of the four pituitary tumors examined by immunohistochemistry. We suggest that a somatic GR defect might have played a pathophysiological role in the tumorigenesis of the corticotropinoma bearing this mutation.

Selective, activity-dependent uptake of histamine into an arthropod photoreceptor.

The synapses made by many arthropod photoreceptors are disinhibitory and use histamine as their transmitter. Because decreases and not increases in the cleft concentration of transmitter constitute the important event at these synapses, a transporter to clear the cleft of histamine would seem particularly crucial to signal transfer. We report here that 3H-histamine is taken up selectively into barnacle photoreceptors by a Na+-dependent mechanism, presumably a transporter. Using light microscopic autoradiography, we observe heavy label over axons and presynaptic terminals of these neurons when they are stimulated during uptake. The radioactivity taken up was identified as 3H-histamine by thin layer chromatography; no metabolites were detected, even after 5 hr. Radiolabeled 5-hydroxytryptamine and GABA are not taken up by the photoreceptor. 3H-histamine uptake into photoreceptors is decreased markedly by an excess of unlabeled histamine and by chlorpromazine and phenoxybenzamine. Unexpectedly for uptake dependent on the NA+ gradient, photoreceptor terminals label more intensely in the light (when depolarized) than in the dark (when hyperpolarized). Glia label more strongly than photoreceptors in dark-incubated preparations. The presence of presynaptic uptake strengthens the evidence that histamine is the neurotransmitter of arthropod photoreceptors and provides a mechanism by which this synapse could recycle transmitter, control its steady-state cleft concentration, and clear it from the cleft in response to decreases in its release from the photoreceptors.