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Peptide and Protein Hormones-----3. Parathyroid Hormone and the Calcitonin Family

Author:N/A    | Post time:2012-05-26

3. Parathyroid Hormone and the Calcitonin Family
Top of page
1. Introduction
2. Gonadoliberin, Thyroliberin, Gonadotropins, Thyrotropin, Inhibin, and Related Hormones
3. Parathyroid Hormone and the Calcitonin Family
4. Corticoliberin – Proopiomelanocortin Cascade
5. Blood Pressure Regulating Peptides
6. Cholecystokinin and Gastrin
7. Secretin Family
8. Neurotensin [1971]
9. Motilin [2005]
10. Pancreatic Spasmolytic Peptide
Parathyroid hormone (PTH) and calcitonin (CT) are secreted from the parathyroid and thyroid glands, respectively. They regulate the plasma calcium level and bone formation. The plasma calcium level is increased by PTH and decreased by CT; PTH stimulates the turnover of bone and CT inhibits it. PTH also stimulates synthesis and release of calcitriol (1,25-dihydroxyvitamin D3) in the kidneys. Like high serum calcium levels, this substance inhibits release of PTH and stimulates the synthesis of calcitonin.

The reproductive hormones described in Chapter Gonadoliberin, Thyroliberin, Gonadotropins, Thyrotropin, Inhibin, and Related Hormones also affect bone formation. TGF- not only stimulates the release of FSH, but also initiates chondrogenesis and osteogenesis (i.e., synthesis of cartilage and bone) [269]. Lack of steroidal sex hormones (estrogen, testosterone, and progesterone), which are important for the release of gonadoliberin, leads to osteoporosis. The chaotic release pattern of PTH appears to be dependent on estrogen levels in women [270].

PTH-related peptide, PTHrP, is formed primarily in tumors and has properties similar to those of PTH. A CT-gene related peptide (CGRP) has also been found. Amylin is a peptide produced by the -cells of the pancreas that has a structural similarity to CGRP.

  3.1. Parathyroid Hormone and PTH-Related Protein [271][272][273]
  Occurrence. Parathyroid hormone (PTH) [9002-64-6] (IUPAC name parathyrin) is formed in the parathyroid gland but is also found in the brain and the pituitary gland. A PTH-related protein (PTHrP) with 141 amino acids (Mr 16 005, h-PTHrP) is formed in tumors that are accompanied by hypercalcemia [274] and in lectin-stimulated lymphocytes [275].

h-, b-, p-, and r-PTH consist of 84 amino acids (Mr 9425, h-PTH); g-PTH has 88 amino acids [276]. The precursor of PTH is prepro-PTH, a peptide containing 31 additional N-terminal amino acids [277].

  Release of PTH. Low plasma calcium increases the synthesis and release of PTH, while high plasma calcium, an infusion of calcium, or a calcium diet [278] lowers the level of PTH. A circadian rhythm is observed with two daily PTH maxima followed by calcium peaks with a delay of 2 h [279]. PTH secretion is also stimulated by insulin-induced hypoglycemia [280], a phosphate-rich diet [281], calcium antagonists [282], a NaCl-rich diet [283], a diet low in vitamin D3 and calcium [284], lithium [285], stress (induced hypocalcemia) [286], noradrenaline [287], histamine, 17--estradiol, and progesterone [288]. In osteoporotic women, the frequency and amplitude of the chaotic pulsatile microsecretion of PTH are greatly reduced after the menopause and estrogen therapy partly regenerates this pulsatile secretion [289].

PTH stimulates the synthesis of calcitriol in the kidneys. Calcitriol inhibits the synthesis and release of PTH [290]. See also  Hormones – Cholecalciferol.

Magnesium slightly inhibits the release of PTH [291]. Dietary magnesium correlates positively with the bone mineral density. The release of PTH is also inhibited by calcium canal activators [282], cholinergic agonists [292], H2-receptor blockers [293], and -receptor blockers [294].

Occurrence of high PTH levels increases with age [295]. Raised levels of PTH are also observed in nephrocalcinosis, osteitis fibrosa cystica, chronic kidney failure [296], liver disease [297], myotonic dystrophy [298], obesity [299], and coronary arterial disease [300].

The release of PTHrP is reduced by glucocorticoids, calcitriol [301], and octreotide [302].

Receptors. PTH – receptor complexes are internalized by bone cells, thus lowering receptor density on the cell surface.

  Biological Effects. The physiological role of PTH is to maintain the extracellular concentration of calcium (1.1 – 1.3 mmol/L) and to prevent hypocalcemia. It is also the principal regulator of bone turnover. PTH stimulates intracellular formation of cAMP and the phosphorylation of intracellular proteins, it also increases intracellular calcium levels.

Low doses of PTH stimulate bone synthesis and high doses result in bone resorption [303]. Hyperparathyroidism causes osteoporosis, while hypoparathyroidism results in increased bone formation [304].

In cultured, osteoblast-like cells, PTH stimulates DNA synthesis [305], alkaline phosphatase activity, amino acid incorporation [306], the release of mediators (e.g., interleukin 6) [307], which stimulate the bone-resorbing activity of the osteoclasts [308]. In osteoclasts, PTH stimulates carbonic anhydrase [309] and acid phosphatase [310].

In vivo, PTH also potentiates bone formation induced by insulin-like growth factor I [311] and the activity of TGF- [312]. In the kidney, PTH stimulates the hydroxylation of 25-hydroxyvitamin D3 to calcitriol which increases enteral absorption of calcium. High plasma calcium levels lower the formation of calcitriol [313] and low calcitriol levels are therefore observed in hyperparathyroid patients with high calcium levels [314]. In the kidneys, PTH causes calcium derived from bone to be returned to the blood and phosphate is excreted in the urine. After prolonged infusion of PTH (> 12 d), calcium and magnesium excretion is increased [315].

PTH lowers blood pressure and causes vasodilatation [316]; cAMP plays a role in the lowering of blood pressure [317]. PTH inhibits the entry of calcium into the cell which may also play a part in its vascular action [318]. PTH-(1 – 34) causes a marked reduction of the blood pressure of spontaneously hypertensive rats [319]. However, about 40 % of patients suffering from hyperparathyroidism are hypertensive because PTH potentiates the hypertensive effect of hypercalcemia [320].

At high calcium concentrations PTH (unlike CT) enhances the arginine-induced secretion of glucagon, which can lead to hyperglycemia. Low PTH doses stimulate the glucose- and calcium-dependent release of insulin in isolated rat pancreas cells, high doses have an inhibitory effect.

Parenteral administration of PTH promotes the development of gastric ulcers, which can be prevented by CT [321]. In contrast, intracerebroventricular application of r-PTH-(1 – 34) inhibits the secretion of gastric acid and the development of gastric ulcers in rats [322].

The properties of PTHrP are similar to those of PTH [323]. It increases the level of calcium and stimulates the formation of calcitriol. The calcium-mobilizing activity of PTHrP-(1 – 34) amide is comparable with that of b-PTH-(1 – 34) [324].

Structure – Activity Relationships. The (1 – 34) N-terminal sequence of PTH contains all the structural requirements for full biological activity. Extension and shortening at the C-terminus of PTH-(1 – 34) results in loss of biological activity. The region (25 – 34) is required for receptor binding, while the first two amino acids at the amino end are of great importance for biological activity. g-PTH-(1 –34), mainly differs structurally from b-PTH between positions 15 and 27 and has only one-tenth the biological activity [325].

Oxidation of Met8 and Met18 in PTH-(1 – 34) abolishes its hypotensive and vasodilating effects without affecting its hypercalcemic effect. Oxidation of PTH-(1 – 34) reduces adenylate cyclase activation in renal blood capillaries, but not in the tubuli [326].

The activity of b-PTH-(1 – 34) is increased by the substitution of Tyr or d-Tyr for Phe34 and the replacement of the two Met residues by Nle. The blocking of the terminal carboxyl group by an amide function also enhances biological activity. Thus, [Nle8,18,d-Tyr34]b-PTH-(1 – 34)amide is about four times more effective than b-PTH-(1 – 34).

  PTH Antagonists. The peptides PTH-(3 – 34) and [Nle8,18,Tyr34]b-PTH-(3 – 34)amide are weak in vitro inhibitors of PTH. [Tyr34]b-PTH-(7 – 34)amide inhibits the PTH-induced excretion of phosphate in urine, cAMP formation [327], and the increase in plasma calcium levels [328]. Cleavage of PTH-(1 – 34) with cathepsin D yields PTH-(8 – 34), which also acts as an antagonist in vitro [329]. Subsitution of Gly12 by d-Trp leads to antagonists that are 10 – 30 times more effective [330].

  Uses. PTH-(1 – 34) has been used in the treatment of osteoporosis. Alternating therapy with calcitriol [331] or sa-calcitonin [332] appears to be especially favorable. PTH-(1 – 34) can also serve as a diagnostic aid to differentiate between pseudohypoparathyroidism and hypoparathyroidism [333].

  3.2. Calcitonin [334]
  Occurence. Calcitonin (CT) [9007-12-9] is mainly synthesized in the C-cells of the thyroid gland, CT-like material is also found in the brain, hypothalamus, pituitary, lungs, thymus, liver, gastrointestinal tract, adrenals, muscle, parathyroid gland, cerebrospinal fluid, seminal fluid [335], and in breast milk [336]. The calcitonins are peptide amides containing 32 amino acids, Mr 3418 (h-CT). Marked structural differences are observed between species. Calcitonin is formed as prepro-CT which contains 109 amino acids. The structures of h-prepro-CT [337] and of g-prepro-CT [338] were elucidated via the cDNA.

  Release of CT. CT is released from the C-cells in response to calcium, strontium, barium, cholinergic peptides (e.g., cholecystokinin and cerulein), secretin, and glucagon. Chronic hypercalcemia has an inhibitory effect on the acute calcium-stimulated release of CT [339]. 17--Estradiol and progesterone stimulate the in vitro secretion of CT from the C-cells of the thyroid glands of eight day old rats [340]. Somatostatin and low plasma levels of calcium inhibit the release of CT. Increased intracellular calcium and cAMP appear to be the second messengers for CT release [341].

Men have a higher plasma CT level than women [342]. A raised plasma level of CT is found in cancer of the thyroid gland [343], heroin addicts [344], and urticaria pigmentosa [345]. A reduced plasma CT level is found in hypothyroidism [346], Cushing\'s syndrome [347], Turner\'s syndrome [348], postmenopausal women [349], and hypogonadal osteoporotic men [350].

Receptors. Receptors for CT in osteoblast-like cells are increased by calcitriol [351] and decreased by CT (via internalization) [352].

  Biological Effects. Low doses of CT stimulate cGMP formation. High doses activate adenylate cyclase (cAMP formation) and inhibit the release of cGMP [353], [354]. In mammals, CT lowers plasma calcium and phosphate levels by inhibiting bone resorption and promoting renal excretion [355].

In women, the ovarian steroid hormones potentiate the hypocalcemic effect of CT [356]. CT exerts antidiuretic and natriuretic effects [357], promoting the excretion of uric acid [358]. It also stimulates 25-hydroxyvitamin D3-1-hydroxylase (i.e., calcitriol synthesis in the kidneys) [359].

The mobility of osteoclasts (giant cells in the bone marrow that are responsible for bone resorption) is inhibited by CT [360] via increased uptake of calcium [361] and phosphate [362]. CT stimulates the proliferation of osteoblasts [363] and activates cartilage synthesis [364].

In humans, CT lowers the insulin level [365], reduces the suppressive effect of glucose on glucagon release, and thus increases blood sugar levels. CT inhibits the release of glucagon induced by arginine or hypoglycemia, as well as glucagon-stimulated glycogenolysis. This may explain why CT lowers plasma glucagon levels and the blood sugar concentration in insulin-dependent diabetics [366]. Intracerebroventricular administration of sa-CT increases the glucose-stimulated release of insulin in rats [367].

Fatty acid synthesis in the liver is increased by CT via calcium-dependent activation of fatty acid synthetase [368] and ATP citrate lyase [369].

CT has both stimulating and inhibitory effects on the hypophyseal hormones. It stimulates the release of the stress hormones ACTH [365] and -endorphin [365] (analgesic effect) and thus release of cortisol from the adrenals [365]. CT inhibits the release of growth hormone [370], prolactin [371], lutropin, follitropin [372], and thyrotropin [373].

Subcutaneous application of CT reduces the stress-induced secretion of gastric acid and the formation of ulcers [374]. In the gastrointestinal tract, CT releases somatostatin, inhibits the release of gastrin [375], and increases motility [376]. Secretion of pancreatic enzymes and the contraction of the gallbladder are also reduced [377]. These effects may be due to action on the CNS because they are also obtained after intracerebroventricular application. Furthermore, central application also causes hypocalcemia in rats [334], delays the emptying of the stomach [378], and reduces absorption of food and water [379]. Intracerebroventricular application of CT increases blood pressure, heart rate [380], and body temperature [381], but intravenously applied CT has no effect [380].

Structure – Activity Relationships. In mammals sa- and anq-CTs produce a 10 – 30 times stronger hypocalcemic effect than that exerted by the mammalian peptides. The C-terminal prolinamide is especially important for biological activity. Substitution of the C-terminal carboxamido group or elimination of the C-terminal proline reduces activity by > 99 %. Acylation of the amino group of the N-terminal cysteine or its substitution by hydrogen slightly increases activity. The N-terminus has a ring structure due to disulfide bond formation between Cys1 and Cys8. This is important for the activity of h-CT, but not for sa-CT [382]. The disulfide structure or the size of the ring is not essential for the activity of anq-CT [383]. The amino acids Ser29 and Thr31 are partly responsible for the high activity of sa-CT. In sa-CT, Val8 can be replaced by Gly without loss of activity. However, this does not apply to Met8 of h-CT [383].

de-Leu16-sa-CT and de-Phe16-h-CT exhibit only one- tenth of the corresponding CT activity in binding tests [384], whereas Tyr22 [383], [385], Leu19, Ser13 [386], Gln20, and Thr21 [385] of sa-CT can be deleted without loss of activity.

Active sa-CT analogues with a stable -helical structure or with a low -helicity exhibit high biological activity [387], [388]. The -helical structure seems to be important for action on the kidney, but not for that on the brain [389].

  Uses. CT can be administered by the subcutaneous, intramuscular, rectal, or intranasal route. Intranasal administration has the fewest side effects [390]. Nasal administration of only 50 IU of sa-CT per day inhibits bone resorption without having a hypoglycemic effect or increasing plasma cAMP levels [391].

sa-CT (Calcitonin L and Karil, Sandoz; Calsynar, Rover), h-CT (Cibacalcin, Ciba-Geigy), p-CT (Calcitonin S, Rover) and, in Japan, [1,7-l-aminosuberic acid]anq- CT (Elcatonin, Carbocalcitonin, and Turbocalcitonin, Toyo, Ioza) are used to treat Paget\'s disease, hypercalcemia, hyperparathyroidism, osteoporosis [392], osteolysis [393], the Sudeck syndrome, acute pancreatitis, chronic polyarthritis [394], and tumorosteolysis. CT is also used as a centrally acting analgesic [395].

  3.3. Calcitonin Gene Related Peptide [396]
  Occurrence. The messenger RNA for calcitonin gene related peptide (CGRP) [83652-28-2] is found primarily in the central and peripheral nervous systems [397], [398]. Circulating CGRP is formed primarily by the perivascular and cardiac nerves.

CGRP consists of 37 amino acids, Mr 3790 (h--CGRP). Two human and rat CGRPs have been observed: -CGRP is coded in the -gene and -CGRP in the -gene [399]. The -gene is also responsible for coding CT.

  Release. CGRP is released by capsaicin [400] and glucocorticoids [401]. Testosterone [402] and - and -opioid receptor agonists [403] inhibit the release of CGRP.

  Biological Effects. CGRP is involved in sensory, motor, and autonomous nervous functions. It stimulates the formation of cAMP.

Intravenous injections result in a rapid decrease of blood pressure and an increase in the heart rate. CGRP is probably of physiological importance for the prevention of cerebral ischemia caused by excessive vasoconstriction and for the control of the peripheral resistance [404]. CGRP stimulates proliferation of human endothelial cells and may be important for the formation of new blood vessels, e.g., in the healing of wounds [405]. Noradrenaline release in mice is stimulated by intracerebroventricular application resulting in increased arterial blood pressure and tachycardia. In the lungs, CGRP exerts a higher bronchoconstricting effect than substance P [406]. Intradermal administration of CGRP causes a more pronounced reddening of the skin than substance P [407]. CGRP may potentiate the release of substance P from primary afferent terminals and promote the transmission of nociceptive information induced by mechanical noxious stimuli [408]. Administration of CGRP to rats inhibits secretion of growth hormone stimulated by a variety of agents [409]. Stress-induced release of prolactin (PRL) is reduced by intraperitoneal or subcutaneous application of CGRP [410].

In the adrenals, CGRP increases the secretion of cortisol and aldosterone and inhibits the release of Met-enkephalin [411].

CGRP appears to be a central mediator of ingestive behavior because central application suppresses food intake. Similar to CT, both the intravenous and the central application of CGRP inhibits gastric acid secretion [412]; this may be a direct effect or/and mediated through the release of somatostatin [413]. CGRP relaxes the intestinal muscle [414] and inhibits the emptying of the stomach in rats [415]. Low doses of - and -CGRP have an antisecretory effect on the epithelium of the colon, but high doses stimulate secretion [416].

CGRP inhibits insulin secretion [417] and insulin-stimulated glycogen synthesis [418], but promotes glycogenolysis [418]. CGRP (and/or amylin) may be responsible for insulin resistance in type II diabetes mellitus.

CGRP inhibits proliferation of cells from the lymph nodes and the spleen of mice [419]. The effect of plasma calcium level and on bone metabolism is similar, but less potent, than that of CT.

Structure – Activity Relationships. The complete structure is required for full biological activity. Acetylation of Lys24, and Lys35, or the N-terminal amino group significantly reduces biological activity [420]. The N-terminal region appears to be important for activity and the C-terminal region for receptor binding.

The N-terminal fragments (1 – 12), (1 – 15), and (1 – 22) of CGRP reduce the blood pressure of rats anesthetized with urethane in a dose-dependent process [421]. h--CGRP-(12 – 37) has a weak antagonistic effect in guinea pig heart preparations [422].

  3.4. Amylin [423]
  Occurrence. Amylin [112938-42-8] (islet amyloid polypeptide), a peptide amide containing 37 amino acids, Mr 3903 (h-amylin), was isolated from amyloid deposits in the pancreatic islet cells of patients suffering from type II diabetes (non-insulin-dependent) [424]. There is a 46 % structural similarity between amylin and CGRP. The disulfide ring and the C-terminal amide are important for full biological activity [425].

Amylin also occurs in normal -cells of various mammals. Not only patients suffering from type II diabetes, but also healthy persons have amylin in their islet -cells. However, amyloid deposits are only found in type II diabetics and not in healthy persons, indicating a pathogenic effect of amylin [426].

  Release. Amylin, like insulin, is released from the rat pancreas by glucose or arginine stimulation [427]. The human plasma level of amylin is low in insulin-dependent diabetes [428].

  Biological Effects. Amylin, like CGRP, inhibits the basal and insulin-stimulated glucose uptake and glycogen synthesis in skeletal muscle [429]. Amylin (and/or CGRP) may be responsible for insulin resistance in type II diabetes mellitus.

Amylin exerts similar effects to CT: it inhibits the osteoclastic resorption of bone at low levels of plasma calcium in rats and rabbits and lowers the plasma calcium level in rats [430].

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