Calcium is critically important for a vast array of cellular functions, as can be seen by a quick look through any physiology book. For example, in this book we discuss the role that Ca2+ plays in muscle mechanics, cardiac electrophysiology, bursting oscillations and secretion, hair cells, and adaptation in photoreceptors, among other things. Clearly, the mechanisms by which a cell controls its Ca2+ concentration are of central interest in cell physiology.
There are a number of Ca2+ control mechanisms operating on different levels, all designed to ensure that Ca2+ is present in sufficient quantity to perform its necessary functions, but not in too great a quantity in the wrong places. Prolonged high concentrations of Ca2+ are toxic. For example, since calcium causes contraction of muscle cells, failure to remove calcium can keep a muscle cell in a state of constant tension (as in rigor mortis).
In vertebrates, the majority of body Ca2+ is stored in the bones, from where it can be released by hormonal stimulation to maintain an extracellular Ca2+ concentration of around 1 mM, while intracellular [Ca2+] is kept at around 0.1 ^M. Since the internal concentration is low, there is a steep concentration gradient from the outside of a cell to the inside. This disparity has the advantage that cells are able to raise their [Ca2+] quickly, by opening Ca2+ channels and relying on passive flow down a steep concentration gradient, but it has the disadvantage that energy must be expended to keep the cytosolic Ca2+ concentration low. Thus, cells have finely tuned mechanisms to control the influx and removal of cytosolic Ca2+.
Calcium is removed from the cytoplasm in two principal ways: it is pumped out of a cell, and it is sequestered into internal membrane-bound compartments such as the mitochondria, the endoplasmic reticulum (ER) or sarcoplasmic reticulum (SR), and secretory granules. Since the Ca2+ concentration in the cytoplasm is much lower than either the extracellular concentration or the concentration inside the internal compartments, both methods of Ca2+ removal require expenditure of energy. Some of this is by a Ca2+ ATPase, similar to the Na+-K+ ATPase discussed in Chapter 2, that uses energy stored in ATP to pump Ca2+ out of the cell or into an internal compartment. There is also a Na+-Ca2+ exchanger in the cell membrane that uses the energy of the Na+ electrochemical gradient to remove Ca2+ from the cell at the expense of Na+ entry (also discussed in Chapters 2 and 3).
Calcium influx also occurs via two principal pathways: inflow from the extracellular medium through Ca2+ channels in the surface membrane and release from internal stores. The surface membrane Ca2+ channels are of several different types: voltage-controlled channels that open in response to depolarization of the cell membrane, receptor-operated channels that open in response to the binding of an external ligand, second-messenger-operated channels that open in response to the binding of a cellular second messenger, and mechanically operated channels that open in response to mechanical stimulation. Voltage-controlled Ca2+ channels are of great importance in other chapters of this book (in particular, when we consider models of bursting oscillations or cardiac cells), and we consider them in detail there. We also omit the consideration of the other surface membrane channels to concentrate on the properties of Ca2+ release from internal stores.
Calcium release from internal stores such as the ER is the second major Ca2+ influx pathway, and this is mediated principally by two types of Ca2+ channels that are also receptors: the ryanodine receptor and the inositol (1,4,5)-trisphosphate (IP3) receptor. The ryanodine receptor, so-called because of its sensitivity to the plant alkaloid ryanodine, plays an integral role in excitation-contraction coupling in skeletal and cardiac muscle cells, and is believed to underlie Ca2+-induced Ca2+ release, whereby a small amount of Ca2+ entering the cardiac cell through voltage-gated Ca2+ channels initiates an explosive release of Ca2+ from the sarcoplasmic reticulum (Fig. 5.1, lower panel). Ryanodine receptors are also found in a variety of nonmuscle cells such as neurons, pituitary cells, and sea urchin eggs. The IP3 receptor, although similar in structure to the ryanodine receptor, is found predominantly in nonmuscle cells, and is sensitive to the second messenger IP3. The binding of an extracellular agonist such as a hormone or a neurotransmitter to a receptor in the surface membrane can cause, via a G-protein link to phospholipase C (PLC), the cleavage of phosphotidylinositol (4,5)-bisphosphate (PIP2) into diacylglycerol (DAG) and IP3 (Fig. 5.1, upper panel). The water-soluble IP3 is free to diffuse through the cell cytoplasm and bind to IP3 receptors situated on the ER membrane, leading to the opening of these receptors and subsequent release of Ca2+ from the ER. Similarly to ryanodine receptors, IP3 receptors are modulated by the cytosolic Ca2+ concentration, with Ca2+ both activating and inactivating Ca2+ release, but at different rates.
As an additional control for the cytosolic Ca2+ concentration, Ca2+ is heavily buffered (i.e., bound) by large proteins, with estimates that approximately 99% of the total cytoplasmic Ca2+ is bound to buffers. The Ca2+ in the internal stores is also heavily buffered.
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