Phosphorylation of the Inositol 1,4,5-Trisphosphate Receptor by Cyclic Nucleotide-dependent Kinases in Vitroand in Rat Cerebellar Slices in Situ

Abstract

Activation of intracellular signal transduction cascades frequently involves increased phosphoinositide hydrolysis following stimulation of phospholipase C. Inositol 1,4,5-trisphosphate (IP 3 ), 1 a second messenger produced by phosphoinositide hydrolysis, mediates Ca 2ϩ release from intracellular stores by binding to IP 3 -sensitive Ca 2ϩ channels, thereby increasing their "open" probability (1). IP 3 receptors derive from at least three different genes, constituting types I, II, and III, which are approximately 70% identical at the amino acid level but differ in distribution and regulation (reviewed in Refs. 1-3). An assembly of four 260-kDa subunits forms the receptor. Each subunit consists of a cytoplasmic, amino-terminal IP 3 binding domain, a coupling domain, and a Ca 2ϩ channel pore of six transmembrane segments (2-4). Type I is further diversified by alternative RNA splicing, resulting in two main forms, of which the longest (SIIϩ, containing the 40 amino acid residues 1693-1732) is specifically expressed in neurons (2). One or more IP 3 receptor forms have been found in virtually all cell types examined (reviewed in Ref. 2), but particularly high amounts of type I IP 3 receptor are seen in smooth muscle cells and in cerebellar Purkinje neurons. Calcium release mediated by IP 3 receptors appears to be an essential step for the induction of long term depression (LTD) in Purkinje cells (5).A number of different mechanisms modulates IP 3 receptor function, including binding of ATP, fatty acids, and calcium (reviewed in Ref. 2); a number of neurodegenerative processes (6, 7); and phosphorylation of the IP 3 receptor by specific protein kinases. cAMP-dependent protein kinase (PKA) phosphorylates the type I IP 3 receptor both in vitro and in vivo (8 -11) and has also been reported to phosphorylate type II and III in intact cells (12). Ca 2ϩ /calmodulin-dependent protein kinase II, protein kinase C and the tyrosine kinase Fyn have also been reported to phosphorylate the type I IP 3 receptor (13)(14)(15)(16)(17). In addition, the receptor may undergo autophosphorylation (18). Early work indicating that the neuronal IP 3 receptor (SIIϩ) can be phosphorylated by cGMP-dependent protein kinase (PKG) (8) was later confirmed by in vitro experiments (19 -21). Likewise, the nonneuronal type I IP 3 receptor (SIIϪ) found in smooth muscle cells, also termed the G 0 protein (22, 23), is a substrate for phosphorylation by both PKA (10) and PKG (19,20,(23)(24)(25). Recent reports of IP 3 receptor phosphorylation by PKA and PKG in hepatocytes (26 -28), kidney cells (11), and platelets (29, 30) support these observations. Phosphorylation of the IP 3 receptor by PKA and PKG represents a possible mechanism for cross-talk whereby cyclic nucleotides can modulate IP 3 -mediated regulation of Ca 2ϩ levels (20, 31). Because cAMP and cGMP levels in most cells are regulated by various extracellular signals, identification of phosphorylation sites labeled by these kinases is of interest. Amino acid sequencing indicated that PKA phosphor...

InsP3R-associated cGMP Kinase Substrate (IRAG) Is Essential for Nitric Oxide-induced Inhibition of Calcium Signaling in Human Colonic Smooth Muscle

“…A cGK-dependent inhibition of InsP 3 production has been described in permeabilized gastric smooth muscle cells (34) and in transfected CHO cells (37). Furthermore, a direct phosphorylation of the InsP 3 receptor by cGKI has been demonstrated in vitro and in vivo (38,39). Finally, an increased reuptake of calcium ions into sarcoplasmatic stores achieved by cGK-dependent activation of sarcoplasmatic Ca 2ϩ -ATPase pumps has been demonstrated in vascular smooth muscle (40 -42).…”

Direct cAMP Signaling through G-Protein-Coupled Receptors Mediates Growth Cone Attraction Induced by Pituitary Adenylate Cyclase-Activating Polypeptide

“…Although an extra- cellular gradient of membrane-permeant cAMP analogs was shown to induce growth cone attraction (Gundersen and Barrett, 1980;Lohof et al, 1992), these reports did not examine other signaling components, e.g., calcium signaling. Recent studies indicated that multiple levels of interactions between Ca 2ϩ and cAMP pathways exist (Eliot et al, 1993;Cooper et al, 1995;Wayman et al, 1995;Mons et al, 1998;Haug et al, 1999;Gorbunova and Spitzer, 2002). Therefore, it was not clear whether growth cone attraction induced by extracellular gradients of cAMP analogs was mediated directly by intracellular cAMP signals or by other pathways affected by cAMP (e.g., Ca 2ϩ ).…”

“…Early investigations using extracellular gradients of membrane-permeant cAMP analogs suggested that the cAMP pathway could influence the direction of growth cone extension (Gundersen and Barrett, 1980;Lohof et al, 1992). However, because Ca 2ϩ -and cAMP-signaling pathways interact (Eliot et al, 1993;Cooper et al, 1995;Wayman et al, 1995;Mons et al, 1998;Haug et al, 1999;Gorbunova and Spitzer, 2002), gradients of cAMP analogs could potentially activate Ca 2ϩ or other signaling pathways to elicit growth cone attraction. Conclusive and direct evidence for local cAMP signals to directly mediate growth cone turning remain to be demonstrated.…”

Dopamine Receptor-mediated Ca2+ Signaling in Striatal Medium Spiny Neurons

“…Neuronal InsP 3 R1 is one of the major substrates of PKA phosphorylation in the brain (29,30). PKA phosphorylates InsP 3 R1 at two sites, Ser-1589 and Ser-1755 (31)(32)(33)(34)(35)(36). PKA phosphorylation activates InsP 3 R1 by increasing the sensitivity of InsP 3 R1 to activation by InsP 3 (35,(37)(38)(39).…”