Parathyroid hormone

Definitions & Key takeaways

Parathyroid hormone (PTH) is a hormone produced by the parathyroid glands and plays a crucial role in regulating the balance of calcium in the body. This hormone is released when the calcium-sensing receptor on parathyroid cells detects a decrease in extracellular calcium.

PTH increases the level of calcium in the blood, by stimulating the bones to release calcium, increasing the absorption of calcium from food in the intestines, and decreasing the excretion of calcium by the kidneys.

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Introduction0:00–0:20

The body’s blood calcium level stays stable thanks to three hormones: parathyroid hormone, vitamin D, and calcitonin. 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.

Calcium Regulation0:20–1:33

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.

Synthesis1:33–2:39

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.

Control2:39–4:09

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.
High intracellular calcium concentration stops the secretory granules that hold PTH from binding to the chief cell’s membrane.
Now, when there’s less calcium in the blood, then the opposite chain of events occurs. Less extracellular calcium binds to the receptor, which means calcium remains in the endoplasmic reticulum, and the secretory granules bind to the cell membrane and PTH gets released!

Functions4:09–6:38

Parathyroid hormone works to increase extracellular calcium in three ways. First, in the bones, PTH binds to receptors on osteoblasts, which are the bone building cells, and gets them to release cytokines.
These cytokines include receptor activator of nuclear factor kappa-B ligand or RANKL for short, and macrophage colony-stimulating factor or M-CSF.
These cytokines help get multiple macrophage precursors to fuse together and form a single osteoclast, which are bone eating cells.
This is kind of like how 5 robot lions join together to form a single Voltron. Osteoclasts breakdown bone, and the two minerals that make up bone - calcium and phosphate, -are released into the blood.
But, in the blood phosphate binds to calciums and form complex calcium which can’t be used cellular processes. To stop this from happening, a second thing that parathyroid hormone will do is bind to receptors on the tubular cells of the kidneys’ proximal convoluted tubules.
This stops the sodium and phosphate cotransporters on the apical surface of the tubular cells from reabsorbing phosphate from the urine.
As a result, phosphate gets lost in the urine, and it’s called phosphaturia. Parathyroid hormone also binds to principal cells of the distal convoluted tubules.
This causes tubular cells to start making more more sodium/ calcium channels, which get embedded on their apical surface and increases reabsorption of calcium from urine.
Third, parathyroid hormone helps the body convert the precursor of vitamin D, called cholecalciferol or D3 into its active form, vitamin D.
Cholecalciferol is synthesized by keratinocyte cells in the epidermal layer of the skin when exposed to sunlight, but can also come from food.
Regardless of the source, cholecalciferol travels to the liver, where the enzyme 25- hydroxylase converts it into 25- hydroxycholecalciferol or calcidiol.
Calcidiol then travels to the proximal tubular cells of the kidneys where the enzyme 1-alpha-hydroxylase, which is also activated by PTH, turns it into 1,25-dihydroxycholecalciferol, also known as calcitriol, or active vitamin D.
Active vitamin D then goes on to the gastrointestinal tract where it enters the enterocytes of the small intestine and increase the activities of the calcium channels on the cell membrane, allowing them in absorb more calcium from food.
Alright, as a quick recap, parathyroid hormone is released when the calcium-sensing receptor on parathyroid cells detect a decrease in extracellular calcium.

Review6:38–7:06

It then works to increase the level of extracellular calcium by stimulating bone resorption, causing phosphaturia and renal calcium reabsorption, as well as calcium absorption in the digestive tract, and altogether, these effects help to keep the extracellular levels of calcium between 8.5 to 10 mg/dl.