Some aspects of calcium pharmacology

Some aspects of calcium pharmacology

Calcium has a dual role in the regulation of cell function: It carries charge and thus contributes to the changes of membrane potential in excitable cells, and it acts as a biochem-ical messenger by directly binding to proteins and modify-ing their functional state. Proteins directly or indirectly af-fected by calcium are very diverse and include enzymes, cy-toskeletal proteins, ion channels, and transcription factors.

The level of free calcium in the cytosol is affected by mul-tiple mechanisms of active and passive transport. These are summarized in Figure 6.1. While the level of calcium in the cytosol varies in time, it is always much lower than in the extracellular space, or than in the mitochondria and ER. These two organelles function as intracellular buffers or reservoirs of calcium. Accordingly, calcium transport systems operating in both directions exist not only at the cytoplasmic membrane but also at the mitochondrial (inner) membrane and the ER.

Many of the physiological effects of Ca⁺⁺ are mediated by the small protein calmodulin (CaM), which upon binding of Ca⁺⁺ changes conformation and binds to multiple ef-fector proteins, including a variety of protein kinases; pro-tein phosphorylation is a widely used means of regulation in signal transduction. Another protein directly activated by Ca⁺⁺ is the protein phosphatase calcineurin, which will participate in the reversal of protein phosphorylation. The spectrum of target proteins for calcium-dependent protein kinases and phosphatases expressed in a given cell will vary and decide on the ultimate effects of calcium regulation in the cell.

Calcium-dependent processes relevant to pharmacological intervention mainly include pace-making in the heart, and contraction in heart and smooth muscle. These are affected by drugs that either act on calcium channels directly, or on other receptors that will have some downstream effect on the cytosolic availability of calcium. Exemples are the β-and α₁-adrenergic receptors (see below).