Homer 1 mediates store- and inositol 1,4,5-trisphosphate receptor-dependent translocation and retrieval of TRPC3 to the plasma membrane

Joo Young Kim, Weizong Zeng, Kirill Kiselyov, Joseph P. Yuan, Marlin H. Dehoff, Katsuhiko Mikoshiba, Paul F. Worley, Shmuel Muallem

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Abstract

Store-operated Ca2+ channels (SOCs) mediate receptor-stimulated Ca2+ influx. Accumulating evidence indicates that members of the transient receptor potential (TRP) channel family are components of SOCs in mammalian cells. Agonist stimulation activates SOCs and TRP channels directly and by inducing translocation of channels in intracellular vesicles to the plasma membrane (PM). The mechanism of TRP channel translocation in response to store depletion and agonist stimulation is not known. Here we use TRPC3 as a model to show that IP3 and the scaffold Homer 1 (H1) regulate the rate of translocation and retrieval of TRPC3 from the PM. In resting cells, TRPC3 exists in TRPC3-H1b/c-IP3Rs complexes that are located in part at the PM and in part in intracellular vesicles. Binding of IP3 to the IP3Rs dissociates the interaction between IP3Rs and H1 but not between H1 and TRPC3 to form IP3Rs-TRPC3-H1b/c. TIRFM and biotinylation assays show robust receptor- and store-dependent translocation of the TRPC3 to the PM and their retrieval upon termination of cell stimulation. The translocation requires depletion of stored Ca2+ and is prevented by inhibition of the IP3Rs. In HEK293, dissociating the H1b/c-IP 3R complex with H1a results in TRPC3 translocation to the PM, where it is spontaneously active. The TRPC3-H1b/c-IP3Rs complex is reconstituted by infusing H1c into these cells. Reconstitution is inhibited by IP3. Deletion of H1 in mice markedly reduces the rates of translocation and retrieval of TRPC3. Conversely, infusion of H1c into H1 -/- cells eliminates spontaneous channel activity and increases the rate of channel activation by agonist stimulation. The effects of H1c are inhibited by IP3. These findings together with our earlier studies demonstrating gating of TRPC3 by IP3Rs were used to develop a model in which assembly of the TRPC3-H1b/c-IP3Rs complexes by H1b/c mediates both the translocation of TRPC3-containing vesicles to the PM and gating of TRPC3 by IP3Rs.

Original languageEnglish
Pages (from-to)32540-32549
Number of pages10
JournalJournal of Biological Chemistry
Volume281
Issue number43
DOIs
StatePublished - 27 Oct 2006

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Inositol 1,4,5-Trisphosphate Receptors
Cell membranes
Cell Membrane
Transient Receptor Potential Channels
Biotinylation
Scaffolds
Homer Scaffolding Proteins
Assays
Chemical activation
Cells

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Kim, Joo Young ; Zeng, Weizong ; Kiselyov, Kirill ; Yuan, Joseph P. ; Dehoff, Marlin H. ; Mikoshiba, Katsuhiko ; Worley, Paul F. ; Muallem, Shmuel. / Homer 1 mediates store- and inositol 1,4,5-trisphosphate receptor-dependent translocation and retrieval of TRPC3 to the plasma membrane. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 43. pp. 32540-32549.
@article{dfa8a3f770de48f1b814d3111f302cd4,
title = "Homer 1 mediates store- and inositol 1,4,5-trisphosphate receptor-dependent translocation and retrieval of TRPC3 to the plasma membrane",
abstract = "Store-operated Ca2+ channels (SOCs) mediate receptor-stimulated Ca2+ influx. Accumulating evidence indicates that members of the transient receptor potential (TRP) channel family are components of SOCs in mammalian cells. Agonist stimulation activates SOCs and TRP channels directly and by inducing translocation of channels in intracellular vesicles to the plasma membrane (PM). The mechanism of TRP channel translocation in response to store depletion and agonist stimulation is not known. Here we use TRPC3 as a model to show that IP3 and the scaffold Homer 1 (H1) regulate the rate of translocation and retrieval of TRPC3 from the PM. In resting cells, TRPC3 exists in TRPC3-H1b/c-IP3Rs complexes that are located in part at the PM and in part in intracellular vesicles. Binding of IP3 to the IP3Rs dissociates the interaction between IP3Rs and H1 but not between H1 and TRPC3 to form IP3Rs-TRPC3-H1b/c. TIRFM and biotinylation assays show robust receptor- and store-dependent translocation of the TRPC3 to the PM and their retrieval upon termination of cell stimulation. The translocation requires depletion of stored Ca2+ and is prevented by inhibition of the IP3Rs. In HEK293, dissociating the H1b/c-IP 3R complex with H1a results in TRPC3 translocation to the PM, where it is spontaneously active. The TRPC3-H1b/c-IP3Rs complex is reconstituted by infusing H1c into these cells. Reconstitution is inhibited by IP3. Deletion of H1 in mice markedly reduces the rates of translocation and retrieval of TRPC3. Conversely, infusion of H1c into H1 -/- cells eliminates spontaneous channel activity and increases the rate of channel activation by agonist stimulation. The effects of H1c are inhibited by IP3. These findings together with our earlier studies demonstrating gating of TRPC3 by IP3Rs were used to develop a model in which assembly of the TRPC3-H1b/c-IP3Rs complexes by H1b/c mediates both the translocation of TRPC3-containing vesicles to the PM and gating of TRPC3 by IP3Rs.",
author = "Kim, {Joo Young} and Weizong Zeng and Kirill Kiselyov and Yuan, {Joseph P.} and Dehoff, {Marlin H.} and Katsuhiko Mikoshiba and Worley, {Paul F.} and Shmuel Muallem",
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Homer 1 mediates store- and inositol 1,4,5-trisphosphate receptor-dependent translocation and retrieval of TRPC3 to the plasma membrane. / Kim, Joo Young; Zeng, Weizong; Kiselyov, Kirill; Yuan, Joseph P.; Dehoff, Marlin H.; Mikoshiba, Katsuhiko; Worley, Paul F.; Muallem, Shmuel.

In: Journal of Biological Chemistry, Vol. 281, No. 43, 27.10.2006, p. 32540-32549.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Homer 1 mediates store- and inositol 1,4,5-trisphosphate receptor-dependent translocation and retrieval of TRPC3 to the plasma membrane

AU - Kim, Joo Young

AU - Zeng, Weizong

AU - Kiselyov, Kirill

AU - Yuan, Joseph P.

AU - Dehoff, Marlin H.

AU - Mikoshiba, Katsuhiko

AU - Worley, Paul F.

AU - Muallem, Shmuel

PY - 2006/10/27

Y1 - 2006/10/27

N2 - Store-operated Ca2+ channels (SOCs) mediate receptor-stimulated Ca2+ influx. Accumulating evidence indicates that members of the transient receptor potential (TRP) channel family are components of SOCs in mammalian cells. Agonist stimulation activates SOCs and TRP channels directly and by inducing translocation of channels in intracellular vesicles to the plasma membrane (PM). The mechanism of TRP channel translocation in response to store depletion and agonist stimulation is not known. Here we use TRPC3 as a model to show that IP3 and the scaffold Homer 1 (H1) regulate the rate of translocation and retrieval of TRPC3 from the PM. In resting cells, TRPC3 exists in TRPC3-H1b/c-IP3Rs complexes that are located in part at the PM and in part in intracellular vesicles. Binding of IP3 to the IP3Rs dissociates the interaction between IP3Rs and H1 but not between H1 and TRPC3 to form IP3Rs-TRPC3-H1b/c. TIRFM and biotinylation assays show robust receptor- and store-dependent translocation of the TRPC3 to the PM and their retrieval upon termination of cell stimulation. The translocation requires depletion of stored Ca2+ and is prevented by inhibition of the IP3Rs. In HEK293, dissociating the H1b/c-IP 3R complex with H1a results in TRPC3 translocation to the PM, where it is spontaneously active. The TRPC3-H1b/c-IP3Rs complex is reconstituted by infusing H1c into these cells. Reconstitution is inhibited by IP3. Deletion of H1 in mice markedly reduces the rates of translocation and retrieval of TRPC3. Conversely, infusion of H1c into H1 -/- cells eliminates spontaneous channel activity and increases the rate of channel activation by agonist stimulation. The effects of H1c are inhibited by IP3. These findings together with our earlier studies demonstrating gating of TRPC3 by IP3Rs were used to develop a model in which assembly of the TRPC3-H1b/c-IP3Rs complexes by H1b/c mediates both the translocation of TRPC3-containing vesicles to the PM and gating of TRPC3 by IP3Rs.

AB - Store-operated Ca2+ channels (SOCs) mediate receptor-stimulated Ca2+ influx. Accumulating evidence indicates that members of the transient receptor potential (TRP) channel family are components of SOCs in mammalian cells. Agonist stimulation activates SOCs and TRP channels directly and by inducing translocation of channels in intracellular vesicles to the plasma membrane (PM). The mechanism of TRP channel translocation in response to store depletion and agonist stimulation is not known. Here we use TRPC3 as a model to show that IP3 and the scaffold Homer 1 (H1) regulate the rate of translocation and retrieval of TRPC3 from the PM. In resting cells, TRPC3 exists in TRPC3-H1b/c-IP3Rs complexes that are located in part at the PM and in part in intracellular vesicles. Binding of IP3 to the IP3Rs dissociates the interaction between IP3Rs and H1 but not between H1 and TRPC3 to form IP3Rs-TRPC3-H1b/c. TIRFM and biotinylation assays show robust receptor- and store-dependent translocation of the TRPC3 to the PM and their retrieval upon termination of cell stimulation. The translocation requires depletion of stored Ca2+ and is prevented by inhibition of the IP3Rs. In HEK293, dissociating the H1b/c-IP 3R complex with H1a results in TRPC3 translocation to the PM, where it is spontaneously active. The TRPC3-H1b/c-IP3Rs complex is reconstituted by infusing H1c into these cells. Reconstitution is inhibited by IP3. Deletion of H1 in mice markedly reduces the rates of translocation and retrieval of TRPC3. Conversely, infusion of H1c into H1 -/- cells eliminates spontaneous channel activity and increases the rate of channel activation by agonist stimulation. The effects of H1c are inhibited by IP3. These findings together with our earlier studies demonstrating gating of TRPC3 by IP3Rs were used to develop a model in which assembly of the TRPC3-H1b/c-IP3Rs complexes by H1b/c mediates both the translocation of TRPC3-containing vesicles to the PM and gating of TRPC3 by IP3Rs.

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U2 - 10.1074/jbc.M602496200

DO - 10.1074/jbc.M602496200

M3 - Article

VL - 281

SP - 32540

EP - 32549

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 43

ER -