22.8 : Feedback Regulation of Calcium Concentration

Calcium is an essential signaling molecule required for various cellular functions. Calcium pumps and ion channels on cell and organellar membranes, such as those on the endoplasmic reticulum (ER), regulate calcium concentrations inside the cell. They remain closed, keeping the cytosolic calcium levels low at a resting state.

Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs stimulate phospholipase C, which produces inositol-1,4,5 trisphosphate (IP3). IP3 binds and opens IP3 gated calcium channels of ER, increasing the cytosolic calcium. The cytosolic calcium levels quickly spike, spreading across the cell by opening nearby IP3 gated calcium channels and ryanodine calcium channels. The sudden rise of calcium ions triggers various cellular responses. One such example is oocyte fertilization. Once a sperm enters the oocyte's zona pellucida and fuses with the plasma membrane, the sperm’s phospholipase stimulates the release of IP3 from the oocyte’s plasma membrane. IP3 opens ER calcium channels, releasing calcium ions and facilitating calcium-induced calcium release (CICR) from the adjacent channels. This forms a calcium wave that moves across the egg starting from the point of sperm entry. The sudden rise in calcium stimulates modification in the egg’s surface and restricts the entry of other sperm. Calcium influx also pushes the zygote towards its first mitotic division by activating cell cycle regulators such as the cyclin-dependent kinases.

As the calcium levels go higher in a cell, the ER calcium channels close, inhibiting the further release of calcium ions. This feedback interaction between calcium ions and IP3 gated calcium channels causes repeated rise and fall in the cytosolic calcium, thus generating calcium oscillations in the cell. The oscillating cytosolic calcium regulates repeated cellular actions, such as the secretion of luteinizing hormone (LH) by the cells of the pituitary gland at every ovulation.

LH controls ovulation and is critical for maintaining female fertility. LH releasing hormone (LHRH) binds GPCRs on the pituitary gland cells' membrane. It triggers the release of calcium ions from ER lumen and facilitates the exocytosis of LH-containing secretory vesicles, releasing LH to the cell exterior.