Calcium is a very common signaling element and plays a critical role in the CNS by regulating the activity of diverse enzymes and facilitating neurotransmitter release (see Figure 1-14). Importantly, excessively high levels of calcium are also a critical mediator of cell death cascades within neurons, necessitating diverse homeostatic mechanisms to regulate intracellular calcium levels very precisely. Thus, although the external level of Ca2+ is approximately 2 mM, the resting intracellular Ca2+ concentrations (Ca2+i) are in the range of 100 nM (that is, 2 x 104 lower) (Rasmussen 1989). Neuronal stimulation by depolarization or receptor activation activates phosphoinositol turnover and increases Ca2+j by one to two orders of magnitude as a result of release of Ca2+ from intracellular stores and/or influx of Ca2+ through ion channels (Rink 1988). Acting via intracellular proteins such as calmodulin and enzymes such as PKC, calcium ions influence synthesis and release of neurotransmitters (Parnas and Segel 1989), receptor signaling (Rasmussen 1986), and neuronal periodicity (Matthews 1986).

Many proteins bind Ca2+; these are classified as either "buffering" or "triggering" and include calcium pumps, calbindin, calsequestrin, calmodulin, PKC, phospholipase A2, and calcineurin (see Figure 1-14). Once stability of intracellular calcium is accomplished, transient low-magnitude changes can serve an important signaling function. Importantly, calcium action is locally mediated; that is, because of the high concentration of calcium-binding proteins, it is estimated that the free Ca2+ ion diffuses only approximately 0.5 L,M and is free for around 50 Usee before encountering a Ca2+-binding protein. Ca2+ is sequestered in the endoplasmic reticulum (which serves as a vast web and framework for Ca2+-binding proteins to capture and sequester Ca2+). Ca2 + buffering/triggering proteins are nonuniformly distributed, and thus there is considerable subcellular variation of Ca2+ concentrations (e.g., near a Ca2 + channel).

Calcium is generally mobilized in one of two ways in the cell, either by mobilization from intracellular stores or by selective diffusion across plasma membrane ion channels (see Figure 1-14). Ca2+ ions pass the membrane through more or less specific channels regulated by changes of membrane potential or transmitter binding. This Ca2+ influx lasts until Ca2+ levels reach a critical level in the submembranal compartment; a potassium current is then activated that repolarizes the membrane. This Ca2+-dependent potassium current represents a strong inhibitory mechanism of the single neuron itself without synaptic input. Its attractiveness for psychiatry lies in its sensitivity to modulatory influences: many amines, peptides, or drugs with relevance in the etiology and/or treatment of these disorders (e.g., norepinephrine, dopamine, corticotrophin-releasing factor [CRF], caffeine, neuroleptics) modify (i.e., increase or decrease) this potassium current. When activation of the potassium pump is decreased, the capacity for negative feedback after excitation becomes impaired and the neuron switches to a state of higher activation, coincidentally with increased calcium influx. Such an overdrive in calcium currents and discharge activity could be a functional prerequisite for states of pathological activity, possibly underlying neuropsychiatric symptoms such as epilepsy, mania, or depression.

Ca2+ released intracellularly is regulated both positively and negatively, resulting in the generation of dynamic Ca2+ waves. Once intracellular Ca2+ levels are increased, this triggers/activates a number of proteins (e.g., adenylyl cyclase type I, CaMKs, PKC, calpain [a protease], calcineurin [a protein phosphatase]). In neurons, Ca2+-dependent processes represent an intrinsic nonsynaptic feedback system that provides the competence for adaptation to different functional tasks (see Figure 1-14). Regulation of intracellular Ca2+ could be of particular relevance to the study of psychiatric disorders, because the same elevation of intracellular Ca2+ may facilitate or inhibit a given function, depending on the target enzyme, the phase of the cell cycle, the intracellular effector protein, and the Ca2+-dependent process. In addition, higher or more sustained increases of intracellular Ca2+ may inhibit the same function that smaller elevations facilitate (Wolff et al. 1977), so that elevated intracellular Ca2+ can produce excessive activation of some systems and inhibition of others. A polymorphism in PPP3CC, a component of the calcium-dependent protein phosphatase calcineurin, has been associated with risk of developing schizophrenia in at least two patient populations (Gerber et al. 2003; Y. L. Liu et al. 2007).

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