Helodermin-like peptides in thyroid C cells: stimulation of thyroid hormone secretion and suppression of calcium incorporation into bone.

Abstract

Helodermin is a vasoactive intestinal peptidelike peptide in the salivary gland venom of the lizard Heloderma suspectum. Helodermin-like immunofluorescence was observed in the parafollicular (C) cells in several mammals and in the C cell homologues of the chicken ultimobranchial gland. Thus, helodermin-like peptides coexist with calcitonin. The results of radioimmunoassay agreed with the immunocytochemical rindings. HPLC of rat thyroid extracts revealed one major peak of helodermin-like immunoreactivity, which eluted in a position close to that of lizard helodermin. Helodermin stimulated basal thyroid hormone secretion and colloid droplet formation in conscious mice. The effect of large doses of helodermin was quite long-lasting and the maximal response occurred after 2-6 hr. In addition, helodermin suppressed the incorporation of calcium into bone in conscious rats. The findings suggest that helodermin-like peptides in C cells may be involved in the local regulation of thyroid hormone secretion and in the maintenance of calcium homeostasis.Helodermin is an amidated 35-amino acid peptide isolated from salivary gland venom of the Gila monster lizard (Heloderma suspectum) (1, 2). Helodermin displays sequence homologies with peptides of the secretin family (1-4). Not surprisingly, helodermin exerts secretin-like and vasoactive intestinal peptide (VIP)-like actions in several biological systems (5-7).Immunochemical analyses have revealed small amounts of helodermin-like material in extracts of brain, salivary glands, and intestines of mammals (8,9). Recently, we showed helodermin-like immunoreactivity in cells in thyroid medullary carcinomas and parafollicular (C)-cell adenomas, where the helodermin-like material was found to coexist with calcitonin (CT) (10). The occurrence of helodermin-like immunoreactivity in normal human C cells suggested that helodermin-like peptides are normal constituents of such cells (10).This study confirms the presence of helodermin-like peptides in thyroid C cells of several mammals. Immunoreactive helodermin was determined by RIA and analyzed by HPLC. The effect of synthetic helodermin on thyroid hormone secretion was tested in mice, while its effect on calcium incorporation in bone was studied in rats. MATERIALS AND METHODSTissue Material. Specimens from thyroid glands (at least ten from each species) were collected for immunocytochemistry and RIA from chickens, mice (NMRI), rats (SpragueDawley), hamsters, guinea pigs, rabbits, pigs, cows, and humans, and ultimobranchial glands (UBG) were collected from chickens. In addition, specimens from salivary glands, heart, lungs, gastrointestinal tract (esophagus, stomach, duodenum, jejunum, and colon), liver, pancreas, spleen, and kidneys of rats (200-g body weight) and pigs were collected.Immunocytochemistry. Helodermin antiserum. Antisera were raised in rabbits against unconjugated synthetic helodermin (Peninsula Laboratories). The peptide, 0.5 mg in 1 ml of 0.9% NaCl, was emulsified with 1.0 ml of Freund's complete adjuvant (Difco)...

Paracrine Regulation of Thyroid-Hormone Synthesis by C Cells

“…In the adult rabbits, bats and guinea pigs, most calcitonin-positive cells also contain somatostatin; however, in adult human and rat thyroid glands, only a small proportion of the calcitonin-positive cells are also somatostatin positive [33]. Similarly, peptides including neuromedin U [34] and helodermin-like peptide [35], have been demonstrated to colocalize with CT in normal C cells. Lately, a new generation of regulatory peptides, similar to those characteristically found in some hypothalamic nuclei, such as TRH [36], CART [37] or ghrelin [38], has increased the long list of substances synthesized by C cells.…”

“…This hypothesis is supported by different features, such as their characteristic 'parafollicular' position, their predominance in the central region of the thyroid lobe -the so-called "C-cell region" [19]-where the most-active follicles of the gland predominate [20], and their implication in the secretion of many different regulatory factors [1,46,56]. Some of these regulatory peptides display an inhibiting action on thyroid hormone secretion, such as calcitonin, calcitonin gene-related peptide (CGRP) and somatostatin [1], whereas others act as local stimulators of thyroid hormone synthesis, such as gastrin-releasing peptide (GRP), helodermin, and serotonin [35,57,58]. For any of those peptides, a requirement to exert an effective paracrine regulation of follicular cells is the presence of their specific receptors in this endocrine cell population.…”

Comparative immunohistochemical study of normal, hyperplastic and neoplastic C cells of the rat thyroid gland

“…Specifically, rat calcitonin-producing cells coexpress other neuroendocrine markers, such as neuron-specific enolase (NSE) (Zabel et al 1987), chromogranin A (Cohn et al 1984), as well as several regulatory factors, such as somatostatin (Van Noorden et al 1977;O'Brian et al 1979;Kameda et al 1982;Zabel 1984;Arias et al 1989), serotonin (Zabel 1984), calcitonin gene-related peptide (CGRP) (Nitta et al 1986;Zabel et al 1987;Kameda 1987), helodermin (Grunditz et al 1989) and C-terminal CCK (Arias et al 1989). However, contrary to human MTC, in which there is an abundant literature on the expression of different substances by neoplastic C cells as these relate to the degree of tumour differentiation and prognosis, the number of publications on the expression pattern of neuroendocrine markers in the putative progression of benign C cells to C-cell carcinoma in rats is very scarce.…”

Vascular effects of helodermin, helospectin I and helospectin II: a comparison with vasoactive intestinal peptide (VIP)

“…Both peptides activate adenylate cyclase in plasma membranes of the rat pancreas but only helodermin induces amylase secretion (Konturek et al, 1989). Helodermin-like peptides occur in high concentrations in the thyroid C cells and in the noradrenaline containing cells of the adrenal medulla in many mammals (Sundler et al, 1988;Grunditz et al, 1989;Bjartell et al, 1989). In the dog, intraarterial infusion of helodermin, like VIP, causes a dosedependent increase in femoral blood flow and intravenous injection produces systemic hypotension and tachycardia (Naruse et al, 1986;Konturek et al, 1989).…”