Parathyroid hormone and vitamin D help increase calcium levels, whereas calcitonin helps lower them. Let’s focus on the role of parathyroid hormone.
The majority of the extracellular calcium, the calcium in the blood and interstitium, is split almost equally into calcium that’s diffusible and calcium that’s not diffusible.
Diffusible calcium is small enough to diffuse across cell membranes and there are two subcategories.
The first is free-ionized calcium, which is involved in all sorts of cellular processes like neuronal action potentials, contraction of skeletal, smooth, and cardiac muscle, hormone secretion, and blood coagulation, all of which are tightly regulated by enzymes and hormones.
The second category is complexed calcium, which is where the positively charged calcium is ionically linked to tiny negatively charged molecules like oxalate and phosphate, which are small anions, that are found in our blood.
The complexed calcium forms a molecule that’s electrically neutral but unlike free-ionized calcium it’s not useful for cellular processes.
Finally there’s the non-diffusible calcium which is bound to large negatively charged proteins like albumin.
The resulting protein-calcium complex is too large and charged to cross membranes, so the non-diffusible calcium is also uninvolved in cellular processes.
Now blood calcium is regulated mainly by parathyroid hormone.
Parathyroid hormone, or PTH, comes from the parathyroid glands, which are 4 pea sized glands buried within the posterior part of the thyroid gland.
Inside the parathyroid glands are parathyroid or chief cells which synthesize a protein called preproPTH in their endoplasmic reticulum.
This long protein chain is 115 amino acid long and contains the parathyroid hormone segment, but also a “pre” segment and a “pro” segment.
In the endoplasmic reticulum an enzyme called signal peptidase cleaves the twenty-five amino acid long “pre”segment off.
Then, the proPTH is then moved to the golgi apparatus where a trypsin like enzyme cleaves off the 6 amino acid “pro” segment, resulting in the final parathyroid hormone - a single-chain polypeptide with 84 amino acids.
At that point, the parathyroid hormone goes from the golgi apparatus, into a secretory vesicle within the cytosol, where it waits to be released.
Normally total blood calcium is between 8.5 to 10 mg/dl.
Changes in calcium levels are detected by a surface receptor on parathyroid cells called the calcium-sensing receptor.
This calcium-sensing receptor is connected by a G protein on the intracellular side of the cell membrane to an enzyme called phospholipase C.
When the extracellular calcium level is normal or higher than normal, lots of calcium binds to the receptor, which activates phospholipase C, or PLC.
Phospholipase C then splits phosphatidyl inositol bisphosphate or PIP2 into two molecules - diacylglycerol or DAG and inositol triphosphate or IP3.
Then IP3 diffuses through the cytoplasm to get to the endoplasmic reticulum, where it binds to a receptor called inositol triphosphate receptor, or Ins3PR on a ligand-gated Ca2+ channel.
This opens the channel and the calcium that is being stored in the endoplasmic reticulum is released into the cytoplasm, making intracellular calcium levels increase.
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