Calcium Homeostasis Pathway Suite

     Calcium (Ca2+) permeates almost every aspect of cellular function. The provision of the Ca2+ signal and its timely removal is mediated by a vast array of channels, pumps and exchangers, also controlling a concentration gradient of four orders of magnitude between the extracellular environment and the cytoplasmic concentration in resting cells. Buffers also contribute to the maintenance of an optimal concentration within the internal milieu of cells and organelles while sensors transmit the initial signaling input.
     The overall diagrams for calcium transport and the calcium/calcium mediated signaling pathways show an overview of the channels, pumps, exchangers and receptors that allow for the flow of Ca2+ in and out of cells and organelles, providing and removing, as necessary, a signal whose availability and effects are further shaped and carried out by buffers and sensors, respectively. Together, they represent the components of the ‘calcium signaling kit’. Calcium signaling via the calcium-sensing receptor probably represents the only instance of Ca2+ acting as a first messenger. The receptor is a G-protein coupled receptor (GPCR) whose signaling inhibits the secretion of parathyroid hormone (PTH) from the parathyroid glands while regulating calcium absorption and water balance in the kidney. It follows that low levels of circulating Ca2+ will not activate the receptor, thus promoting the release of PTH whose signaling, via its own G-protein coupled receptor, plays important roles in calcium and phosphate homeostasis. As a second messenger, Ca2+ achieves its many functional aspects by binding to and activating a number of sensors, of which calmodulin is a prominent representative. Binding of Ca2+ triggers conformational changes that lead to exposure of a hydrophobic patch which then mediates the interaction of calmodulin with its many downstream effectors. The calmodulin dependent kinases and the phosphatase calcineurin are some of the most important targets of calmodulin. Of the three multifunctional kinases, calmodulin dependent kinase 2 (Camk2) exerts the broadest spectrum of functions. The other two kinases, kinase 1 and 4, need an upstream activating kinase, together acting in a cascade-like fashion reminiscent of MAPK. The diagram image shows the relative positions of terms representing these pathways in the pathway ontology tree; highlighted are the pathways with interactive diagrams currently available and presented in this suite.

Calcium transport pathway

Calcium/calcium-mediated signaling pathway

A wide array of channels, pumps, receptors and exchangers make available or remove, as necessary, the Ca2+ ion, one of the most versatile signaling molecules in living systems. Click here to explore the complex pathway of Ca2+ transport. The providers/regulators of the signal, exemplified in the calcium transport pathway along with the buffers and sensors that further shape the availability of the ion and its messaging, represent the components of the ‘calcium signaling kit’,  and are presented in this overall diagram. Click here to explore this complex circuit.

Calcium signaling pathway via the calcium-sensing receptor

Parathyroid hormone signaling pathway

Calcium/calmodulin dependent kinase 2 signaling pathway

In what is probably the only instance of Ca2+ acting as a first messenger, it activates a G-protein coupled receptor whose signaling opposes the release of the parathyroid hormone from the parathyroid glands while regulating Ca2+ absorption and water balance in the kidneys. Click here to explore this important signaling module. The parathyroid hormone (PTH) engages the PTHr1 receptor, a G-protein coupled receptor whose signaling regulates Ca2+ and phosphate reabsorption by the kidneys. Specifically, it increases Ca2+  reabsorption leading to an increased release of the metal ion into the circulation and diminishes phosphate reabsorption leading to its excretion. In the bone, PTH exerts both catabolic and anabolic effects. Click here to explore this important signaling pathway.
Four genes and more than 30 splice variants are responsible for the broad spectrum of functions exerted by calmodulin dependent protein kinase 2 (Camk2) signaling. The pathway plays central roles in the excitation-contraction (ECC) and excitation-transcription (E-T) coupling in the heart and in long-term potentiation (LTP) and memory formation in the brain. Click here to explore this complex and important signaling module.

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