Pharmacology of inositol trisphosphate receptors

Abstract

In almost all cells, cytosolic Ca(2+) is a crucial intracellular messenger, regulating many cellular processes. In non-excitable as well as in some excitable cells, Ca(2+) release from the intracellular stores into the cytoplasm is primarily initiated by the second messenger inositol 1,4,5-trisphosphate (IP(3)), which interacts with the IP(3) receptor (IP(3)R), a tetrameric intracellular Ca(2+)-release channel. This review focuses on the pharmacological modulation of the various functionally important sub-domains of the IP(3)R, including the IP(3)-binding domain, calmodulin-binding sites, adenine nucleotide-binding sites and the sites for interaction for FK506-binding proteins and other regulators. We will particularly focus on the pharmacological tools that interfere with these domains and discuss their relative specificity for the IP(3)R, thereby indicating their potential usefulness for unraveling the complex functional regulation of the IP(3)R.

The 12 kDa FK506-binding protein, FKBP12, modulates the Ca2+-flux properties of the type-3 ryanodine receptor

“…This is compatible with previous findings showing that in the presence of the immunosuppressant FK506, which disrupts FKBP12 interaction, RyR1 and RyR2 channels become more sensitive to activators, such as caffeine, Ca 2+ or ATP (Timerman et al, 1993;Brillantes et al, 1994;Mayrleitner et al, 1994;Ondrias et al, 1998;Gaburjakova et al, 2001). The use of FK506, however, must be viewed with caution, since this drug has multiple effects on intracellular Ca 2+ homeostasis independent of RyRs (Bultynck et al, 2003), including effects on the sarcoand endoplasmic reticulum Ca 2+ -ATPases (Bultynck et al, 2000;Bilmen et al, 2002), the passive Ca 2+ leak (Bultynck et al, 2002), Ca 2+ -influx channels (Burley and Sihra, 2000), voltage-operated Ca 2+ channels (Yasutsune et al, 1999), Ca 2+ -activated K + channels (Terashima et al, 1998) and the outward K + current (duBell et al, 1997). Disruption of FKBP12 interaction with wt RyR3 by FK506 treatment led, in our hands, to non-specific effects (data not shown), probably related to Ca 2+ -pump inhibition (Bultynck et al, 2000) and to effects of the solvent ethanol on the activation of RyR3 channels (Table 1).…”

“…Both channels are encoded by three different genes, leading to the expression of three different isoforms. The activity of these channels is tightly regulated by a plethora of cellular factors, such as Ca 2+ , pH, redox state, ATP and associated proteins (Mackrill, 1999;Patel et al, 1999;Bultynck et al, 2003).The type-1 RyR (RyR1) is predominantly expressed in skeletal muscle cells and is physiologically activated upon depolarisation of the plasma membrane by direct interaction with the dihydropyridine receptor. The type-2 RyR (RyR2) is predominantly expressed in cardiac muscle cells and is physiologically activated by Ca 2+ influx through voltagedependent L-type channels.…”

“…Both channels are encoded by three different genes, leading to the expression of three different isoforms. The activity of these channels is tightly regulated by a plethora of cellular factors, such as Ca 2+ , pH, redox state, ATP and associated proteins (Mackrill, 1999;Patel et al, 1999;Bultynck et al, 2003).…”

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

“…[20,21]). It is believed that subtle variations in the sensitivity of the three IP 3 R isoforms to such allosteric regulators can modulate the biophysical properties of the channels.…”

Endothelin-1 enhances nuclear Ca2+ transients in atrial myocytes through Ins(1,4,5)P3-dependent Ca2+ release from perinuclear Ca2+ stores

“…This means that, at the same concentration of Ins(1,4,5)P 3 , nuclear Ins(1,4,5)P 3 receptors might be activated, whereas cytoplasmic Ins(1,4,5)P 3 receptors are not. As Ins(1,4,5)P 3 receptors are modulated by a variety of factors (Bultynck et al, 2003), differences in Ins(1,4,5)P 3 sensitivity between cytoplasmic and nuclear Ins(1,4,5)P 3 receptors could be caused by subcellular differences in the concentrations or activities of these modulatory factors. Alternatively, the local [Ins(1,4,5)P 3 ] near nuclear Ins(1,4,5)P 3 receptors might be higher than in the vicinity of cytoplasmic Ins(1,4,5)P 3 receptors.…”