Parathyroid hormone (PTH) is a polypeptide hormone secreted by the parathyroid glands, which are typically four small glands located behind the thyroid in the neck. The primary function of PTH is to tightly maintain calcium homeostasis, ensuring that the concentration of calcium ions in the blood remains within a very narrow and regulated range. Calcium is essential for numerous physiological processes, including muscle contraction, nerve impulse transmission, and blood clotting. PTH works as the main hormonal defense against hypocalcemia, or low blood calcium levels, by mobilizing calcium from various body stores and promoting its retention.
The Role of Calcium-Sensing Receptors
The parathyroid glands utilize a sophisticated molecular sensor to constantly monitor the level of circulating calcium, acting as the body’s calcium-ion “thermostat.” This sensor is known as the Calcium-Sensing Receptor (CaSR), a type of G-protein-coupled receptor found on the surface of the parathyroid gland’s chief cells. The CaSR is directly responsible for detecting fluctuations in the concentration of ionized calcium in the extracellular fluid.
When calcium levels are high, calcium ions bind to the CaSR, activating an intracellular signaling pathway that immediately suppresses the release of stored PTH. Conversely, when the concentration of calcium falls, fewer calcium ions bind to the CaSR, which turns off this inhibitory signal. This deactivation rapidly triggers the chief cells to synthesize and secrete PTH into the bloodstream.
The CaSR allows for the immediate modulation of PTH secretion. This receptor controls the acute release of the stored hormone and also influences the long-term synthesis of PTH and the proliferation of the parathyroid cells themselves. The CaSR serves as the molecular linchpin that translates the extracellular calcium concentration into the appropriate hormonal response.
The Negative Feedback Mechanism Regulating PTH
The mechanism that regulates the release of parathyroid hormone is a negative feedback loop. This mechanism is characterized by the rising blood calcium concentration acting to shut down the initial stimulus. The loop begins when a drop in serum calcium is detected by the CaSR on the parathyroid glands.
In response to this low calcium signal, the parathyroid glands increase the rate of PTH secretion into the circulation. This surge of PTH then acts on target organs—bone and kidney—to raise the calcium level back toward the normal set point. As the concentration of calcium in the blood begins to rise, it binds more frequently to the CaSR on the parathyroid chief cells.
The binding of calcium to the CaSR sends an inhibitory signal that turns off the PTH secretion. By increasing calcium levels, the hormone negates the original stimulus that caused its release, which completes the negative feedback cycle and maintains calcium homeostasis.
How Parathyroid Hormone Raises Blood Calcium
Parathyroid hormone acts on three main target sites—the bone, the kidneys, and the intestines—to increase the concentration of calcium in the blood. The hormone’s actions on bone involve stimulating the release of calcium from the body’s largest calcium reservoir. PTH indirectly promotes the activity of osteoclasts, the cells responsible for bone resorption, or the breakdown of the mineralized bone matrix.
PTH binds to osteoblasts, the bone-forming cells, which then release signaling molecules like RANKL. This molecular signal stimulates the differentiation and activity of osteoclast precursors, leading to the rapid dissolution of bone tissue and the subsequent release of stored calcium and phosphate into the bloodstream. This process serves as a quick mechanism to mobilize calcium when blood levels fall.
The kidneys are another direct target, where PTH executes two distinct functions. First, it enhances the reabsorption of calcium from the filtered fluid, specifically in the distal convoluted tubule and the collecting duct, reducing calcium loss in the urine. Second, PTH promotes the excretion of phosphate by inhibiting its reabsorption in the proximal tubules. High phosphate levels can bind with calcium and reduce the amount of free, ionized calcium in the blood.
Finally, PTH indirectly increases calcium absorption through its action on Vitamin D metabolism. PTH stimulates the enzyme 1-alpha-hydroxylase in the kidneys, which converts the inactive form of Vitamin D into its biologically active form, calcitriol (1,25-dihydroxycholecalciferol). Calcitriol then travels to the small intestine, where it acts to increase dietary calcium absorption into the body.