Calcium levels, regulation

PTH has a dual effect on bone cells, depending on the temporal mode of administration given intermittently, PTH stimulates osteoblast activity and leads to substantial increases in bone density. In contrast, when given (or secreted) continuously, PTH stimulates osteoclast-mediated bone resorption and suppresses osteoblast activity. Further to its direct effects on bone cells, PTH also enhances renal calcium re-absorption and phosphate clearance, as well as renal synthesis of 1,25-dihydroxy vitamin D. Both PTH and 1,25-dihydroxyvitamin D act synergistically on bone to increase serum calcium levels and are closely involved in the regulation of the calcium/phosphate balance. The anabolic effects of PTH on osteoblasts are probably both direct and indirect via growth factors such as IGF-1 and TGF 3. The multiple signal transduction... 

Calcium-dependent regulation involves the calcium-calmodulin complex that activates smooth muscle MLCK, a monomer of approximately 135 kDa. Dephosphorylation is initiated by MLCP. MLCP is a complex of three proteins a 110-130 kDa myosin phosphatase targeting and regulatory subunit (MYPT1), a 37 kDa catalytic subunit (PP-1C) and a 20 kDa subunit of unknown function. In most cases, calcium-independent regulation of smooth muscle tone is achieved by inhibition of MLCP activity at constant calcium level inducing an increase in phospho-rMLC and contraction (Fig. 1). 

Calcitonin is a naturally occurring mammalian hormone that plays a major role in regulation of calcium levels. It inhibits bone resorption by binding to osteoclast receptors. Compared with mammalian calcitonin, salmon calcitonin has high potency and extended duration of action. Although commercial formulations of calcitonin-salmon actually are synthetic and not derived from salmon, they contain the same amino acid sequence as calcitonin of salmon origin. 

Around 99% of calcium is contained in the bones, whereas the other 1% resides in the extracellular fluid. Of this extracellular calcium, approximately 40% is bound to albumin, and the remainder is in the ionized, physiologically active form. Normal calcium levels are maintained by three primary factors parathyroid hormone, 1,25-dihydroxyvitamin D, and calcitonin. Parathyroid hormone increases renal tubular calcium resorption and promotes bone resorption. The active form of vitamin D, 1,25-dihydroxyvitamin D, regulates absorption of calcium from the GI tract. Calcitonin serves as an inhibitory factor by suppressing osteoclast activity and stimulating calcium deposition into the bones. 

The release of calcitonin from the thyroid is regulated by plasma calcium levels through negative feedback. An increase in the level of calcium in the... 

The final mechanism of action of PTH involves the activation of vitamin D3 through the stimulation of la-hydroxylase in the kidney. In the gastrointestinal tract, vitamin D3 is essential for the absorption of calcium. Enhanced absorption of calcium from dietary sources serves to further increase the concentration of calcium in the blood. Many foods, in particular, dairy products, which are rich in calcium, are fortified with vitamin D. The release of PTH from the parathyroid glands is regulated by plasma calcium levels through negative feedback. A decrease in the level of calcium in the blood stimulates the secretion of PTH and an increase in the calcium level in the blood inhibits it. 

Regulation of glycogen synthesis and degradation is essentially the same in the liver and muscle, but there are a couple of wrinkles. Glycogen degradation is also activated in muscle in response to the rise in intracellular calcium levels that accompanies contraction. This is achieved by... 

Parathyroid hormone (PTH) regulates calcium levels in blood and bone remodeling. The activation domain of that 84-amino acid polypeptide locates around the N-terminal (1-34 amino acids). Parathyroid hormone receptor is a typical G-protein coupled receptor, which is coupled to both adenyl cyclase/cAMP and PLCy/IP3/cytosolic Ca2+ intracellular signaling pathways. In order to identify the structural elements involved in the peptide hormone binding and signal initiation, Chorev et al. employed a photoaffinity scanning approach. The N-terminal amino acids were successively deleted or modified and the new N-terminus was replaced for photoreactive Bpa. The most active peptide ana-... 

Plasma calcium level is precisely regulated by three hormones e.g. parathormone, calcitonin and calciferol (which is a active form of vitamin D). They control its absorption, exchange with bone and excretion. 

NO has a significant effect on vascular smooth muscle tone and blood pressure. Numerous endothelium-dependent vasodilators, such as acetylcholine and bradykinin, act by increasing intracellular calcium levels, which induces NO synthesis (Figure 19-2). Mice with a knockout mutation in the eNOS gene display increased vascular tone and elevated mean arterial pressure, indicating that eNOS is a fundamental regulator of blood pressure. The effects of vasopressor drugs are increased by inhibition of NOS. 

The drug indirectly alters the regulation of intracellular calcium levels via protein kinase C and can alter the transcription of gene- (downregulating) encoding enzymes (e.g., ATP/ADP translocase) and those involved in energy production and specific for cardiac tissue. 

Vitamin D3, also called cholecalciferol, is normally formed in the skin from 7-dehydrocholesterol in a photochemical reaction driven by the UV component of sunlight (Fig. 10-20). Vitamin D3 is not itself biologically active, but it is converted by enzymes in the liver and kidney to 1,25-dihydroxycholecalciferol, a hormone that regulates calcium uptake in the intestine and calcium levels in kidney and bone. Deficiency of vitamin D... 

The major location of calcium in the body is in the skeleton, which contains more than 90% of the body calcium as phosphate and carbonate. Bone resorption and formation keeps this calcium in dynamic equilibrium with ionized and complexed calcium in blood, cellular fluids and membranes. Homeostasis is mainly regulated by the parathyroid hormone and vitamin D which lead to increased blood calcium levels, and by a thyroid hormone, calcitonin, which controls the plasma calcium concentration J5 Increasing the concentration of calcitonin decreases the blood calcium level, hence injections of calcitonin are used to treat severe hyperalcaemia arising from hyperparathyroidism, vitamin D intoxication or the injection of too high a level of parathyroid extract. High levels of calcitonin also decrease resorption of calcium from bone. Hypocalcaemia stimulates parathyroid activity, leading to increased release of calcium from bone, reduction in urinary excretion of calcium and increased absorption of calcium from the intestine. Urinary excretion of phosphate is enhanced. 

The expression of genes involved in cell proliferation and cell death is regulated by nuclear transcriptional factors. NFAT (Nuclear Factor of Activated T cells) proteins are a family of Ca2+-dependent transcription factors (Crabtree, 2001), whose nuclear translocation and transcriptional activity is regulated by Ca2+/calmodulin-dependent protein phosphatase, calcineurin (Crabtree, 2001). Thus, NFAT proteins can potentially be activated by diverse stimuli that lead to increased intracellular calcium levels. The NF-kB (nuclear factor kappa B) family... 

Preliminary studies also suggested that calcium channel blockers my increase the risk of cancer.10,28 Intracellular calcium levels are important in regulating cell division. By modifying calcium influx, calcium channel blockers could conceivably accelerate cell proliferation and lead to cancerous growths. Fortunately, the carcinogenic potential of these drugs has not been proven conclusively by subsequent studies.21 Hence, calcium channel blockers continue to be used cautiously but effectively in large numbers of patients. 

The primary factor regulating PTH release is the level of calcium in the bloodstream.42 Parathyroid gland cells appear to act as calcium sensors that monitor circulating calcium levels. As circulating calcium levels fall below a certain point, PTH secretion is increased. Conversely, elevated plasma calcium titers inhibit PTH secretion. The ability of PTH to control plasma calcium levels and regulate bone mineral metabolism is discussed in more detail in Chapter 31... 

PTH works with two other primary hormones— calcitonin and vitamin D—in regulating calcium homeostasis. These three hormones, as well as several other endocrine factors, are all involved in controlling calcium levels for various physiologic needs. How these hormones interact in controlling normal bone formation and resorption is of particular interest to rehabilitation specialists. Regulation of bone mineral homeostasis and the principal hormones involved in this process are presented in the following section. 

Consequently, bone is a rather dynamic tissue that is constantly undergoing changes in mineral content and internal structure. The balance between bone resorption and formation is controlled by the complex interaction of local and systemic factors. In particular, several hormones regulate bone formation and help maintain adequate plasma calcium levels. The primary hormones involved in regulating bone mineral homeostasis are described below. 

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