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Calcium is a second messenger that regulates almost all cellular functions. In cardiomyocytes, calcium plays an integral role in many functions including muscle contraction, gene expression, and cell death. Inositol 1,4,5-trisphosphate receptors (IP 3 Rs) are a family of calcium channels that are ubiquitously expressed in all tissues. In the heart, IP 3 Rs have been associated with regulation of cardiomyocyte function in response to a variety of neurohormonal agonists, including those implicated in cardiac disease. Notably, IP 3 R activity is thought to be essential for mediating the hypertrophic response to multiple stimuli including endothelin-1 and angiotensin II. In this review, we will explore the functional implications of IP 3 R activity in the heart in health and disease. [ABSTRACT FROM AUTHOR]

The inositol 1,4,5 trisphosphate (IP3 ) receptor (IP3 R) is a Ca 2+ release channel that responds to the second messenger IP3 . Exquisite modulation of intracellular Ca 2+ release via IP3 Rs is achieved by the ability of IP3 R to integrate signals from numerous small molecules and proteins including nucleotides, kinases, and phosphatases, as well as nonenzyme proteins. Because the ion conduction pore composes only ∼5% of the IP3 R, the great bulk of this large protein contains recognition sites for these substances. Through these regulatory mechanisms, IP3 R modulates diverse cellular functions, which include, but are not limited to, contraction/ excitation, secretion, gene expression, and cellular growth. We review the unique properties of the IP3 R that facilitate cell-type and stimulus-dependent control of function, with special emphasis on protein-binding partners. [ABSTRACT FROM AUTHOR]

Inositol 1,4,5‐trisphosphate receptors (IP3Rs) are a family of intracellular Ca2+ channels that exist as homo‐ or heterotetramers. In order to determine whether the N‐terminal ligand‐binding domain is in close physical proximity to the C‐terminal pore domain, we prepared microsomal membranes from COS‐7 cells expressing recombinant type I and type III IP3R isoforms. Trypsin digestion followed by cross‐linking and co‐immunoprecipitation of peptide fragments suggested an inter‐subunit N‐ and C‐terminal interaction in both homo‐ and heterotetramers. This observation was further supported by the ability of in vitro translated C‐terminal peptides to interact specifically with an N‐terminal fusion protein. Using a 45Ca2+ flux assay, we provide functional evidence that the ligand‐binding domain of one subunit can gate the pore domain of an adjacent subunit. We conclude that common structural motifs are shared between the type I and type III IP3Rs and propose that the gating mechanism of IP3R Ca2+ channels involves the association of the N‐terminus of one subunit with the C‐terminus of an adjacent subunit in both homo‐ and heterotetrameric complexes. [ABSTRACT FROM AUTHOR]

Inositol 1,4,5-trisphosphate receptors (IP3Rs) are a family of intracellular Ca2+ channels that exist as homo- or heterotetramers. In order to determine whether the N-terminal ligand-binding domain is in close physical proximity to the C-terminal pore domain, we prepared microsomal membranes from COS-7 cells expressing recombinant type I and type III IP3R isoforms. Trypsin digestion followed by cross-linking and co-immunoprecipitation of peptide fragments suggested an inter-subunit N- and C-terminal interaction in both homo- and heteratetramers. This observation was further supported by the ability of in vitro translated C-terminal peptides to interact specifically with an N-terminal fusion protein. Using a 45Ca2+ flux assay, we provide functional evidence that the ligand-binding domain of one subunit can gate the pore domain of an adjacent subunit. We conclude that common structural motifs are shared between the type I and type III IP3Rs and propose that the gating mechanism of IP3R Ca2+ channels involves the association of the N-terminus of one subunit with the C-terminus of an adjacent subunit in both homo- and heterotetrameric complexes. [ABSTRACT FROM AUTHOR]

Tumor cells strategically down-regulate Fas receptor expression to evade immune attack and up-regulate expression of Fas ligand to promote apoptosis of infiltrating T lymphocytes. Many pathways leading to apoptotic cell death require calcium release from inositol 1,4,5-trisphosphate receptors (IP3Rs). Here, we show that Fas-dependent killing of Jurkat T lymphoma cells by SW620 colon cancer cells requires calcium release from IP3R. General suppression of IP3R signaling significantly reduced SW620-mediated Jurkat cell apoptosis. Significantly, a specific inhibitor of apoptotic calcium release from IP3R strongly blocked lymphocyte apoptosis. Thus, selective pharmacological targeting of apoptotic calcium release from IP3R may enhance tumor cell immunogenicity. [ABSTRACT FROM AUTHOR]