Calcium and inositol trisphosphate IP3

Calcium ions represent one of the most common and versatile second messengers found inside a cell. Changes in the cytosolic free Ca2+ concentration affect numerous intracellu-lar events ranging from the short-term modulation of accessory proteins to long-lasting changes in gene expression. Besides crossing the cell membrane through voltage-gated channels from the outside, Ca2+ can enter the cytosol from internal stores in response to many environmental signals. Several G protein-linked receptors activate a PTX-insensitive G protein to stimulate the activity of membrane-bound phospholipase CP (PLCP). This enzyme specifically cleaves phosphatidylinositol(4,5)bisphosphate (PIP2) in the membrane to generate two important second messengers, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) (Berridge 1993; Clapham 1995). IP3 triggers Ca2+ release from internal stores by binding to and opening specific channels found along the surface of the endo-plasmic reticulum (ER). Signals are transduced throughout the cell by stimulating the activity of various enzymes such as calcium-sensitive or calcium/calmodulin-dependent kinases and phosphatases, several of which modify the functions of ion channels. Protein kinase C (PKC) represents a well-known example of a kinase whose activity is partially dependent on the binding of Ca2+ to its regulatory domain. Another Ca2+-sensitive kinase, calcium/calmodulin-dependent kinase II (CaM kinase II), is expressed at high levels throughout different regions of the central nervous system and has been linked to the phosphorylation of various channels and receptors (Schulman et al. 1995; Ghosh and Greenberg 1995; Soderling 1996). There is considerable evidence that activated CaMK II enhances AMPA receptor currents in dissociated cultures of hippocampal as well as spinal cord neurons (McGlade-McCulloh etal. 1993; Kolaj etal. 1994). The intracellular perfusion of dorsal horn neurons with an activated form of CaMK II leads to significant increases in AMPA-induced macroscopic currents which are not observed with denatured forms of the enzyme. Similar findings have been obtained with CA1 pyramidal neurons recorded in brain slice preparations (Lledo et al. 1995). This effect is thought to occur at least partially through the direct phosphorylation of glutamate receptors by CaMK II in response to Ca2+ elevations in the cell (McGlade-McCulloh etal. 1993; Tan etal. 1994).

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