Defining the minimal structural requirements for partial agonism at the type I <i>myo</i>‐inositol 1,4,5‐trisphosphate receptor

Wilcox, Robert G.; Fauq, Abdul H.; Kozikowski, Alan P.; Nahorski, Stefan R.

doi:10.1016/s0014-5793(96)01540-2

Cited by 16 publications

(19 citation statements)

References 28 publications

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“…Ins ( 2) using a previously described method (27). The [Ca 2ϩ ] of the cytosol-like buffer was determined using fura-2 (28) and buffered to 120 -190 nM with EGTA.…”

Section: Methodsmentioning

confidence: 99%

Rapid Down-regulation of the Type I Inositol 1,4,5-Trisphosphate Receptor and Desensitization of Gonadotropin-releasing Hormone-mediated Ca2+ Responses in αT3–1 Gonadotropes

Willars¹,

Royall²,

Nahorski³

et al. 2001

Journal of Biological Chemistry

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Despite no evidence for desensitization of phospholipase C-coupled gonadotropin-releasing hormone (GnRH) receptors, we previously reported marked suppression of GnRH-mediated Ca 2؉ responses in ␣T3-1 cells by pre-exposure to GnRH. This suppression could not be accounted for solely by reduced inositol 1,4,5-trisphosphate (Ins(1,4,5)P 3 ) responses, thereby implicating uncoupling of Ins(1,4,5)P 3 production and Ca 2؉ mobilization (McArdle, C. A., Willars, G. B., Fowkes, R. C., Nahorski, S. R., Davidson, J. S., and Forrest-Owen, W. (1996) J. Biol. Chem. 271, 23711-23717). In the current study we demonstrate that GnRH causes a homologous and heterologous desensitization of Ca 2؉ signaling in ␣T3-1 cells that is coincident with a rapid (t1 ⁄2 < 20 min), marked, and functionally relevant loss of type I Ins(1,4,5)P 3 receptor immunoreactivity and binding. Furthermore, using an ␣T3-1 cell line expressing recombinant muscarinic M 3 receptors we show that the unique resistance of the GnRH receptor to rapid desensitization contributes to a fast, profound, and sustained loss of Ins(1,4,5)P 3 receptor immunoreactivity. These data highlight a potential role for rapid Ins(1,4,5)P 3 receptor down-regulation in homologous and heterologous desensitization and in particular suggest that this mechanism may contribute to the suppression of the reproductive system that is exploited in the major clinical applications of GnRH analogues.

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“…Ins ( 2) using a previously described method (27). The [Ca 2ϩ ] of the cytosol-like buffer was determined using fura-2 (28) and buffered to 120 -190 nM with EGTA.…”

Section: Methodsmentioning

confidence: 99%

Rapid Down-regulation of the Type I Inositol 1,4,5-Trisphosphate Receptor and Desensitization of Gonadotropin-releasing Hormone-mediated Ca2+ Responses in αT3–1 Gonadotropes

Willars¹,

Royall²,

Nahorski³

et al. 2001

Journal of Biological Chemistry

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“…The most critical structural feature of InsP 3 is its vicinal D-4,5-bisphosphate motif, with the 5-phosphate being the dominant partner in receptor interaction (Wilcox et al, 1997). The 1-phosphate also contributes to the receptor interaction specificity (Nahorski and Potter, 1989), potency (Willcocks et al, 1989;Jenkinson et al, 1992), and efficacy (Wilcox et al, 1995(Wilcox et al, , 1997. The hydroxyl group in 6-position appears to make a major contribution to the binding interactions with the receptor (Safrany et al, 1991), whereas FIG.…”

Section: C)mentioning

confidence: 97%

“…18), the interaction of InsP 3 with its receptor is highly stereospecific, with the D-isomer being over 1000 times more potent than the L-isomer (Nahorski and Potter, 1989). The most critical structural feature of InsP 3 is its vicinal D-4,5-bisphosphate motif, with the 5-phosphate being the dominant partner in receptor interaction (Wilcox et al, 1997). The 1-phosphate also contributes to the receptor interaction specificity (Nahorski and Potter, 1989), potency (Willcocks et al, 1989;Jenkinson et al, 1992), and efficacy (Wilcox et al, 1995(Wilcox et al, , 1997.…”

Section: C)mentioning

confidence: 99%

Pharmacological Modulation of Sarcoplasmic Reticulum Function in Smooth Muscle

2004

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“…The phosphate group at position 1 seems to be one determinant of the agonistic property of Ins(1,4,5)P 3 [163], but modifications of the 3-hydroxyl positions also resulted in a decreased efficacy [164]. One of the best partial agonist described so far is the 3-fluorinated 4,5-phosphorothioate analogue of Ins(1,4,5)P 3 [3F-Ins(1)P(4,5)PS 3 ] (19), which displays a relatively high affinity with modest intrinsic activity [163]. Highly potent, noninositol phosphate agonists have been recently isolated from fungal cultures and were structurally identified as adenophostins [165] (Fig.…”

Section: Agonist-induced Calcium Influxmentioning

confidence: 99%

“…Most investigators have used heparin to anatgonize Ins(1,4,5)P 3 action on the receptor, and certainly heparin can block Ins(1,4,5)P 3 -induced Ca 2+ release in cell-free systems or when injected into cells [163]. However, heparin is a very nonselective tool and will bind to a large number of proteins with basic residues to inhibit their function.…”

Section: Agonist-induced Calcium Influxmentioning

confidence: 99%

Pharmacology of Phosphoinositides, Regulators of Multiple Cellular Functions

Balla¹

2001

CPD

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Inositol phospholipids represent a small fraction of the phospholipids present in all cellular membranes with remarkable importance in regulating various cell functions. They are synthesized from phosphatidylinositol by sequential phosphorylations on the several hydroxyls of the inositol ring to create polyphosphoinositides that function either as docking sites to promote formation of molecular signaling complexes, or serve as precursors for soluble inositol polyphosphates that act as diffusible intracellular messengers. Phosphoinositides are involved in the control of many processes, including membrane traffic, endo- and exocytosis, mitogenesis and apoptosis. Pharmacological tools have helped to clarify many details of phosphoinositide metabolism and have unveiled the roles of these lipids in the control of specific signaling pathways. However, because of their pleiotropic functions it has been questionable whether pharmacological manipulation of inositide formation and metabolism can be of therapeutic value. This review briefly summarizes the means by which inositide functions have been pharmacologically manipulated, and discusses possibilities for specifically targeting certain aspects of their regulatory functions.

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Defining the minimal structural requirements for partial agonism at the type I myo‐inositol 1,4,5‐trisphosphate receptor

Cited by 16 publications

References 28 publications

Rapid Down-regulation of the Type I Inositol 1,4,5-Trisphosphate Receptor and Desensitization of Gonadotropin-releasing Hormone-mediated Ca2+ Responses in αT3–1 Gonadotropes

Rapid Down-regulation of the Type I Inositol 1,4,5-Trisphosphate Receptor and Desensitization of Gonadotropin-releasing Hormone-mediated Ca2+ Responses in αT3–1 Gonadotropes

Pharmacological Modulation of Sarcoplasmic Reticulum Function in Smooth Muscle

Pharmacology of Phosphoinositides, Regulators of Multiple Cellular Functions

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