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Calcium plays a vital role within the human body, and is involved in various cellular functions. The skeleton acts as a large reservoir of calcium that can be mobilized by various hormones, and approximately 99% of the body's calcium is found in the bones in the form of calcium phosphate salts (hydroxyapatites) which give strength and rigidity to the skeleton. As well as this calcium is a key component of the teeth and connective tissue and has a central function in cell-cell adhesion, control of neural excitability and stimulus-secretion coupling among various other roles. Due to the importance of calcium as a regulatory ion, it is crucial that the body maintains adequate calcium levels. This is achieved through regulatory hormones acting on the bone, kidney and intestine which include metabolites of cholecalciferol (vitamin D), parathyroid hormone, and calcitonin. The hormonal changes can only be activated if the calcium sensing receptors (CaSR) on the parathyroid gland detect changes in plasma calcium. If plasma calcium levels are imbalanced it may lead to medical disorders. One example includes hyperparathyroidism which is the over activity of the parathyroid glands that stimulates excess release of parathyroid hormone (PTH). Cinacalcet is a drug that acts as a calcimimetic (an agent that mimics the stimulatory action of Ca2+ by allosteric activation of calcium-sensing receptors.) known to provide potential therapy for individuals with primary and secondary hyperparathyroidism; inhibiting PTH secretion and ultimately lowering calcium levels. This drug also has potential applications other then maintaining calcium homeostasis in tissues and cells expressing CaSR such as in the neurones, brain, heart etc, thus it may play a beneficial role in other functions within the body.
Normal Calcium Homeostasis
The body regulates calcium homeostasis by the combined effects of three hormones; vitamin D, PTH and calcitonin, which are released in response to a range of physiological stimuli related to changes in plasma calcium. Vitamin D itself is not biologically active, but it undergoes hydroxylation within the kidney to form hormone known as 1,25-dihydroxycholecalciferol . This hormone helps to regulate calcium in the body if it is too low, by stimulating the absorption of ingested calcium and phosphate from the gastrointestinal tracts as well as increasing the renal tubular absorption of calcium and phosphate. It does this by binding to specific nuclear receptors; this interaction in turn causes an increase in the rate of calcium-binding proteins believed to transport calcium around the cell, thus increasing plasma calcium levels.
The parathyroid hormone (PTH) is the second hormone involved in maintaining calcium levels, and is secreted by the parathyroid glands. There are four of these situated in the posterior surfaces of the lateral lobes of the thyroid gland. PTH acts on the bones, gut and kidneys, and functions to raise plasma calcium levels and reduce plasma phosphate levels. If the plasma calcium level decreases PTH secretion rises. Normal levels of PTH are important for maintaining the skeleton as it promotes the production of osteoblasts which are the cells responsible for the accretion of new bone, and the calcification of the bone matrix. PTH also stimulates the reabsorption of calcium in the distal tubule and decreases reabsorption of phosphate in the proximal tubules as a means of increasing plasma calcium levels if it is too low.
Lastly the hormone calcitonin, secreted by the parafollicular or C- cells of the thyroid gland counteracts the effects of PTH, and instead decreases blood calcium levels if they are detected to be too high during normal homeostasis. Calcitonin regulates plasma calcium by inhibiting calcium absorption by the intestines, and preventing bone osteoclast action, thus inhibiting bone reabsorption so minerals are not released into the plasma.
Calcium sensing receptor (CaSR)
To instigate the hormonal changes that result in the alteration of serum calcium levels, a highly sensitive mechanism for detecting small fluctuations in serum calcium concentrations is required. This is attained through the interaction of calcium with a specific cell surface receptor known as the calcium sensing receptor (CaSR). This receptor is a G-protein-coupled receptor with a characteristic structure consisting of seven transmembrane helices, an intracellular C-terminal and a large extracellular N-terminal domain (ECD) which is believed to be the site of calcium binding. As well as this there are extracellular loops which contain two highly conserved cysteine residues that form disulfide bridges to stabilise the receptor structure, these extracellular regions are able to be glycosylated. The CaSR can be found in the parathyroid, kidney, the intestines and the brain. The interaction of calcium with the extracellular domain of the parathyroid CaSR leads to a series of events in which the activated CaSR stimulates various types of G proteins from a number of G protein subfamilies, primarily Gαq /11 and Gαi, consequently leading to a range of cellular responses such as the stimulation of phospholipase Cβ (PLCβ), and most importantly the release of intracellular Ca2+. Therefore we can deduce that the calcium-sensing receptors play an important role in the regulation of calcium levels.
If the function of the CaSR is altered it is inevitable that this will have an effect on calcium homeostasis just as it has been shown in various inherited disorders of calcium homeostasis such as hypocalcaemia and hyperparathyroidism. These conditions can be as a result of loss-of-function mutations of CaSR which decrease the sensitivity of CaSR to extracellular calcium, in doing so PTH levels also increased. This is due to the fact that during normal homeostasis the binding of calcium to the calcium sensing receptor inhibits PTH secretion from the parathyroid gland, however in this case as the receptors are desensitised, calcium does not bind to the receptors thus resulting in over secretion of PTH from the parathyroid glands. One mutation of the CaSR has shown to result with a new cysteine residue in the first extracellular loop. As we know that disulfide bridges in the extracellular loop are important in maintaining the receptor structure, there is a possibility that this new cysteine of this mutation forms an aberrant bridge with one of the cysteine residue and this disrupts the vital relationship of the transmembrane domains thus preventing signal transduction, and ultimately desensitising the receptor. Alternatively the loss of function of the receptor may be due to the fact that this mutation creates an abnormal disulfide bridge which may destabilise the protein and/or reduce the expression of its glycosylated forms on its cell surface.
Calcimimetics - Cinacalcet
Diseases that are caused by mutations and disrupt the function of CaSR can be treated by drugs that target the altered receptors and compensate for some CaSR mutations; these drugs are known as calcimimetics. Calcimimetics are molecules known to activate the calcium-sensing receptor (CaSR) as well as inhibit parathyroid hormone (PTH) secretion by mimicking or potentiating the effects of extracellular calcium, in particular on parathyroid cells. There are CaSR's situated on the surface of the parathyroid cells which react to changes in plasma ionised calcium levels increasing the secretion of PTH (for example if calcium levels dropped, i.e. the CaSR not activated) or stopping PTH secretion (for example if plasma calcium levels were increased i.e. the CaSR activated.) Calcimimetics such as the drug cinacalcet function as an allosteric activator of the calcium sensing receptor (G-protein linked receptor) by binding directly to the receptor membrane spanning domains, thus it increases the sensitivity of the calcium sensing receptor to extracellular calcium, ultimately reducing PTH secretion The CaSR is generally very specific due to its ability to selectively adjust responses only in tissues in which the endogenous agonist applies its physiological effects. This function of cinacalcet has been shown to be effective in the treatment of individuals with primary and secondary hyperparathyroidism and hypercalcaemia.
Effect of increased PTH levels on Bones, Kidneys and Intestine
Cinacalcet is highly important in treating individuals suffering from hypercalcaemia and hyperparathyroidism as high levels of calcium and PTH can have negative effects on bones, the kidneys and intestine. Symptoms of hypercalcaemia include nausea, vomiting, tiredness, muscle weakness, loss of bone, kidney stones amongst many others. High levels of PTH can have long term and short term effects on bone metabolism. The short term effect includes the initial rapid loss of calcium from the readily releasable pool of calcium on the bone surface which is released in the blood; this effect is believed to be brought upon by a combination of PTH as well as vitamin D as some evidence displays . The long term effects of increased PTH levels stimulate resorption of stable bone by the oseteoclasts (degradation of bone), thus adding a great amount of mineral to the extracellular fluid. The skeletal effects of increased PTH levels vary between individuals, but generally demineralisation of the skeleton is often found. In such cases there is bone pain, fractures of the long bone and compression fractures of the spine. Cysts composed of osteoclasts may also be present. The effects of hypercalcaemia and hyperparathyroidism on the bones are severe, as the action of osteoclasts and osteoblasts are coupled, and a disruption in this balance leads to disruption in normal bone structure therefore it is important that calcium levels are regulated.
Excessive levels of PTH also have adverse effects on the kidneys. PTH stimulates the reabsorption of calcium in the distal tubule and decreases reabsorption of phosphate in the proximal tubules. The net effect of these actions consequently increases the plasma calcium and decreases the plasma phosphate concentration. The fall in plasma phosphate levels further promotes the increase in plasma calcium levels by reducing the quantity of phosphate ions available to bind with calcium. Although the increased rate of calcium reabsorption in the tubules, there is still an increase in the amount of calcium excreted in the urine due to the fact the filtered calcium load is very high. As the kidney is also responsible for making vitamin D (1,25-dihydroxycholecalciferol) this further increases calcium concentrations as vitamin D increases calcium uptake from the gut as well as increasing calcium reabsorption in the kidney. If the plasma calcium persists in high levels it may have an impaired effect on the renal function as the soft tissues within the kidneys become calcified leading to disorders such as kidney stones.
Hyperparathyroidism does not appear to exert a direct effect on the intestine, although it does promote synthesis of vitamin D in the kidney, which as we know enhances intestinal absorption of ingested calcium.
Effect of Calcimimetics on the Bones, Kidneys and Intestine
Calcimimetics such as cinacalcet have shown to be therapeutically beneficial in disorders that affect calcium homeostasis and skeletal integrity due to its ability to increase the sensitivity of CaSR to extracellular calcium.
Research has provided evidence that CaSR is expressed in bone cells known as osteoclasts  and osteoblasts and that they could have vital functional roles within these cells. Osteoclasts are involved in bone degradation and osteoblasts are associated with bone formation. Cinacalcet is believed to reduce bone resorption (which decreases PTH secretion) thus it stimulates the proliferation of osteoblasts. Research has shown that increased levels of calcium combined with calcimimetic agents inhibit the formation of osteoclasts like cells in vitro. There have been however discrepancies in reports about the presence of CaSR on osteoblasts, although most reports support the view that CaSR is present on osteoblasts. Those reports that do support the idea that the presence of CaSR on osteoblasts have shown elevated levels of calcium display various physiological actions on osteoblast-like cells such as stimulating their proliferation and chemotaxis. Other research showed that with the use of cinacalcet bone fracture risk was significantly reduced by 54%, biochemical markers of bone turnover were decreased, and bone mineral density was improved.
As the kidneys play a key role in calcium homeostasis and PTH stimulates renal calcium reabsorption, we would expect that the decreased PTH levels due to calcimimetics would cause lower levels of renal calcium absorption. The CaSR is present in the proximal tubule, the thick ascending limb of Henle's loop, the distal convoluted tubule as well as the cortical collecting duct along the nephron , which are the sites of calcium transport in the kidneys. Additionally research has shown that cinacalcet inhibits both passive paracellular and active transcellular absorption of calcium in mouse cortical thick ascending limbs thus decreasing the reabsorption of calcium in the kidneys. However other studies have showed that cinacalcet did not affect the rate of disappearance of calcium form the blood indicating the possibility that cinacalcet does not induce hypocalcaemia by increasing urinary calcium excretion; hypocalcaemia results from the decrease influx of calcium into the circulation not from the increased influx.
As well as the kidneys, the intestine is another major organ involved in calcium homeostasis and research on rats shows the CaSR is present in the duodenum, jejunum and andileum . However it has been observed that the infusion of cinacalcet has no effect on daily fecal calcium excretion in normal rats regardless of the existence of hypocalcaemia. This finding is consistent with research that showed cinacalcet is has no direct effect on serum 1,25-dihydroxycholecalciferol, thus it is indicated that the cinacalcet-induced hypocalcaemia is solely due to the reduced mobilisation of calcium under conditions of increased calcitonin and decreased PTH secretion.
Cinacalcet has also shown to be successful in improving PTH control in patients suffering from primary and secondary hyperparathyroidism. Primary hyperparathyroidism is defined by the enlargement of one or more of the parathyroid glands increasing PTH secretion, thus also increasing plasma calcium levels. Secondary hyperparathyroidism is when the body produces excess PTH as calcium levels are low. If the parathyroid gland continues to secrete excess PTH despite the calcium level being restored to normal, this is known as tertiary hyperparathyroidism and occurs especially in patients with kidney problems. Research has shown that when cinacalcet was given to haemodialysis patients, PTH and serum calcium were simultaneously reduced. It is important to differentiate between the effects of calcimimetic agents and calcium-containing phosphate binders or Vitamin D. Although Vitamin D can successfully suppress high levels of PTH, it does so at the cost of increasing serum calcium and phosphate. Therefore it is the combination of cinacalcet and Vitamin D that allow PTH levels to be suppressed whilst simultaneously avoiding excessive elevations of serum calcium, phosphate and PTH.
Other functions of cinacalcet beyond maintaining calcium homeostasis
The calcimimetic agent cinacalcet has other functions beyond its role in maintaining calcium homeostasis in the body due to the distribution of the calcium sensing receptor. The CaSR is not only expressed in organs controlling homeostasis (e.g. parathyroid glands, kidneys, intestines, osteoclasts, osteoblast etc.) but also in numerous other tissues and cell types including cardiomyocytes, neurons, gastrointestinal system, pancreas etc.) Although the functional significance of these CaSR in other tissues and cells other than those involved in calcium homeostasis is not fully understood, research indicates that they act as a regulator of diverse cellular functions such as intracellular communication, maintenance of membrane potential, gene expression etc.
It has been proposed that the CaSR has an important function in mediating cell to cell communication within pancreatic islets to direct insulin secretory response with the aid of calcimimetics. Cells communicate locally via gap junctions where adjacent cells physically connect and allow the free flow of ions and small molecules or through the release of local paracrine messengers. Changes in the calcium influx or efflux pathways across the plasma membrane cause a change in the extracellular concentration of calcium, which ultimately is sufficient enough to activate the CaSR on an adjacent cell. Research shows this may be due to the fact that calcium leaving stimulated cells recruit neighbouring cells and create a widespread tissue response. The activation of the CaSR using calcimimetics that are receptor specific is thought to enhance insulin secretion from human islets. Usually it is unlikely that in the absence of stimulatory glucose concentrations the receptor mediated stimuli will initiate insulin secretion, however the activation of CaSR through calcimimetic agents such as cinacalcet rapidly increases insulin secretion. This process occurs when glucose induced changes in one cell stimulate the secretion of insulin from surrounding cells expressing CaSR through the corelease of divalent cations which generally improve secretory function.
Cinacalcet also has other functions on the heart due to the CaSR receptor being expressed in several components of the cardiovascular system. Animal studies indicate that these receptors are present in atrial and ventricular myocytes (cardiomyocytes), as well as several vessel types such as perivascular nerves, endothelial cell and vascular smooth muscle cells . It has been shown the CaSR can regulate activity of ion channels in other cells thus there is a possibility that the CaSR in the cardiomyocytes may also regulate ion channels and therefore the membrane potential. Additionally the CaSR in the vessels have been shown to regulate vascular tone thus could explain the observation to why calcium induces vasodilation. Supporting this hypothesis the calcimimetic agent cinacalcet lowers blood pressure and improves cardio morphology (capillary density, fibrosis) in nephrectomised rats. However parathyroidectomy had a similar effect, therefore it is unclear as to whether the effects of calcimimetics are due to reduced PTH concentrations or whether the calcimimetics affect target structures directly. The discovery of the CaSR in key components of the cardiovascular system is important as it is suggestive of possible roles for the receptor in heart and vascular physiology and due to the increasing clinical use of calcimimetics it is important we understand these roles for other potential therapeutics.
In conclusion it is clear that the role of calcimimetic agents such as cinacalcet are vital as a therapeutic agents in individuals whom have a dysfunction in the normal processing of calcium homeostasis, such as those suffering from primary or secondary hyperparathyroidism in which there is PTH secretion. Cinacalcet's unique ability to mimic or potentiate the effect of extracellular calcium on the parathyroid cells inhibits PTH secretion in those suffering from hyperparathyroidism, and thus proves itself as a useful drug in helping treat such individuals. Changes in plasma calcium are detected by specific calcium sensing receptors (CaSR) that are vital in promoting hormonal changes to correct any imbalance in plasma calcium. This receptor can however become mutated and therefore desensitised to plasma calcium, leading to disorders such as hyperparathyroidism; cinacalcet's ability to allosterically bind to this receptor helps reduce the negative effects that elevated levels of PTH have on the bones kidneys and intestines. Cinacalcet is not only is useful in regulating calcium homeostasis, but also plays other roles in other tissues and cell types expressing CaRS such as neurones, oligodendrocytes, cardiomyocytes, pancreas cells etc. Research has shown that calcimimetics may have some role in increasing insulin secretion and improving secretory functions in the pancreas, as well as possibly having some role in heart and vascular physiology in which it lowers blood pressure. Overall the use of cinacalcet has seen to be very beneficial as a therapeutic agent, and ongoing research suggests many more positive potential uses of cinacalcet in tissues expressing CaSR.
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