The body uses microscopic sensors to maintain a stable internal environment, much like a thermostat regulates a home’s temperature. In the body, proteins called receptors act as sensors for specific molecules, and the Calcium-Sensing Receptor (CaSR) is a primary example.
The CaSR is a protein on the surface of various cells that functions as the body’s “calcium thermostat,” detecting small fluctuations in blood calcium concentration. A precise calcium balance is necessary for nerve operation, muscle contraction, and maintaining strong bones. The CaSR ensures this balance is upheld by initiating signals that adjust calcium levels.
How the Calcium Sensing Receptor Regulates Calcium
The primary sites where the CaSR manages the body’s calcium are the parathyroid glands and kidneys. The parathyroid glands are four small glands in the neck that produce Parathyroid Hormone (PTH), a main regulator of calcium. The CaSR is expressed on the surface of cells within these glands, where it monitors blood calcium concentration.
This system operates on a negative feedback loop. When blood calcium levels rise, the CaSRs on parathyroid cells become activated, signaling the cells to decrease PTH production and release. Reduced PTH levels then instruct the kidneys to excrete more calcium into the urine and signal the bones to slow the release of their calcium stores.
Conversely, when blood calcium levels fall, the CaSRs become less active. This inactivity is interpreted by the parathyroid glands as a signal to increase PTH secretion. Higher PTH levels instruct the kidneys to conserve calcium by reducing its loss in urine and stimulate the bones to release stored calcium into the bloodstream.
The CaSR in the kidneys also plays a direct role. Receptors on kidney tubule cells sense calcium concentrations in the blood and in the fluid that will become urine. When these receptors detect high calcium, they directly inhibit the reabsorption of calcium in a part of the kidney. This provides a second, PTH-independent mechanism to increase calcium excretion and prevent levels from getting too high.
The Role of CaSR Beyond Calcium Balance
While its function in the parathyroid glands and kidneys is a primary part of calcium management, the CaSR is expressed in many other tissues, revealing its involvement in a wider range of bodily processes. The CaSR acts as a versatile sensor, responding not only to calcium but also to molecules like amino acids and changes in pH.
In the gastrointestinal tract, the CaSR is found on cells from the stomach to the colon. It helps regulate processes like gastric acid secretion and the release of hormones that aid digestion. By sensing nutrient levels in the gut, the CaSR can influence the secretion of hormones like cholecystokinin, which aids pancreatic enzyme release and creates a feeling of fullness.
The CaSR is also present on bone cells, including osteoblasts (which build new bone) and osteoclasts (which break down bone tissue). In this context, calcium acts through the CaSR to stimulate osteoblast activity, promoting bone formation. It also inhibits osteoclast activity, thereby slowing bone resorption and helping manage the skeleton’s role as a calcium reservoir.
The CaSR is found throughout the central nervous system, including in brain areas like the hippocampus. Its presence in the brain suggests a role in processes such as neuronal excitability, synaptic transmission, and fluid balance. For example, in the hippocampus, the CaSR may play a part in memory and learning by modulating how neurons communicate.
Disorders of the Calcium Sensing Receptor
Since the CaSR is a primary regulator of blood calcium, genetic mutations that alter its function can lead to health disorders. These conditions are caused by mutations in the CASR gene and are categorized as either “loss-of-function” or “gain-of-function.” Using the thermostat analogy, a loss-of-function mutation creates a receptor that is “stuck on cold,” while a gain-of-function mutation results in one that is “stuck on hot.”
Loss-of-function mutations make the CaSR underactive, meaning it requires a higher level of blood calcium than normal to become activated. The parathyroid glands therefore incorrectly perceive that calcium levels are always low. This leads to the continuous secretion of PTH, which causes the bones to release excess calcium and the kidneys to retain it, resulting in chronically high blood calcium (hypercalcemia).
The most common disorder from a loss-of-function mutation in one gene copy is Familial Hypocalciuric Hypercalcemia (FHH). Individuals with FHH have elevated blood calcium but low calcium in their urine because the underactive CaSR in the kidneys also causes them to retain too much calcium. In rare cases where an infant inherits two mutated gene copies, a more severe condition called Neonatal Severe Hyperparathyroidism (NSHPT) occurs.
Gain-of-function mutations make the CaSR overactive, similar to an overly sensitive thermostat. The receptor signals to the parathyroid glands that calcium levels are perpetually high, even when they are normal or low. This signal shuts down PTH secretion, leading to low blood calcium (hypocalcemia) and high urine calcium (hypercalciuria), as the kidneys are instructed to excrete it. This condition is known as Autosomal Dominant Hypocalcemia (ADH).
Medical Treatments Targeting the CaSR
The understanding of the CaSR’s function has enabled the development of drugs that directly target it. These medications modulate the receptor’s activity, providing a therapeutic approach for certain disorders of calcium metabolism. The primary class of drugs for this purpose is known as calcimimetics.
Calcimimetics work by mimicking the effect of calcium on the receptor. These drugs, such as Cinacalcet, bind to the receptor to increase its sensitivity to calcium. This action tricks the CaSR on the parathyroid glands into thinking there is more calcium in the blood than there actually is.
By making the CaSR more sensitive, calcimimetics cause the parathyroid glands to reduce their secretion of PTH. This effect is useful in treating secondary hyperparathyroidism, which often develops in patients with chronic kidney disease (CKD). In CKD, mineral imbalances lead to excessive PTH production, and calcimimetics help bring these levels under control.
These drugs are also used to manage hypercalcemia in patients with parathyroid carcinoma, a cancer where the tumor produces uncontrolled amounts of PTH. By suppressing PTH secretion, calcimimetics can help lower high blood calcium levels. The development of these targeted therapies highlights how knowledge of a receptor can translate into clinical treatments.