Vesl/Homer proteins regulate ryanodine receptor type 2 function and intracellular calcium signaling

Westhoff, Jens H.; Hwang, Sung-Yong; Duncan, R. Scott; Ozawa, Fumiko; Volpe, Pompeo; Inokuchi, Kaoru; Koulen, Peter

doi:10.1016/s0143-4160(03)00112-x

Cited by 65 publications

(65 citation statements)

References 30 publications

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“…In contrast to RyR1, Homer-1c decreased the function of RyR2 as it reduced both the cyclic ADP ribose-and the caffeineinduced Ca 2+ release mediated by RyR2 from cardiac sarcoplasmic reticulum microsomes (37). The reduction in RyR2 activity results from a decrease in the open probability of the RyR2 channel.…”

Section: Ryanodine Receptor Type 2 (Ryr2)mentioning

confidence: 96%

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Homer/Vesl Proteins and Their Roles in CNS Neurons

Ehrengruber

Kato

Inokuchi

et al. 2004

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Section: Ryanodine Receptor Type 2 (Ryr2)mentioning

confidence: 96%

“…Another type of calcium-activated calcium channel, RyR2, physically interacts with Homer-1c (37). In contrast to RyR1, Homer-1c decreased the function of RyR2 as it reduced both the cyclic ADP ribose-and the caffeineinduced Ca 2+ release mediated by RyR2 from cardiac sarcoplasmic reticulum microsomes (37).…”

Section: Ryanodine Receptor Type 2 (Ryr2)mentioning

confidence: 99%

Homer/Vesl Proteins and Their Roles in CNS Neurons

Ehrengruber

Kato

Inokuchi

et al. 2004

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“…In addition to the mGluRs, many Ca 2+ signaling proteins express Homer ligands and bind Homer. Among them are the scaffolding protein Shank [8], PLCβ [16,17], IP 3 receptors (IP 3 Rs) [15,18], TRPC channels [15,18], ryanodine receptors (RyRs) [19][20][21][22] and selective L-type Ca 2+ channel isoforms [23][24][25].…”

Section: Homers Localization and Binding To Ca 2+ Signaling Proteinsmentioning

confidence: 99%

“…Indeed, measurement of Ca 2+ release in permeabilized skeletal muscle fibers and the activity of RyRs reconstituted into lipid bilayers show that Homer1 activates the skeletal and cardiac muscle RyR isoforms RyR1 [19][20][21] and RyR2 [22]. In addition, infusion and expression of H1a, but not H1b, activates the L-type Ca 2+ current in neocortex pyramidal neurons [23].…”

Section: Homer1 and Ryrsmentioning

confidence: 99%

Homer proteins in Ca2+ signaling by excitable and non-excitable cells

et al. 2007

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Homers are scaffolding proteins that bind Ca 2+ signaling proteins in cellular microdomains. The Homers participate in targeting and localization of Ca 2+ signaling proteins in signaling complexes. However, recent work showed that the Homers are not passive scaffolding proteins, but rather they regulate the activity of several proteins within the Ca 2+ signaling complex in an isoform specific manner. Homer2 increases the GAP activity of RGS proteins and PLCβ that accelerate the GTPase activity of Gα subunits. Homer1 gates the activity of TRPC channels, controls the rates of their translocation and retrieval from the plasma membrane and mediates the conformational coupling between TRPC channels and IP 3 Rs. Homer1 stimulates the activity of the cardiac and neuronal Ltype Ca 2+ channels Ca v 1.2 and Ca v 1.3. Homer1 also mediates the communication between the cardiac and smooth muscle ryanodine receptor RyR2 and Ca v 1.2 to regulate E-C coupling. In many cases the Homers function as a buffer to reduce the intensity of Ca 2+ signaling and create a negative bias that can be reversed by the immediate early gene form of Homer 1. Hence, the Homers should be viewed as the buffers of Ca 2+ signaling that ensure a high spatial and temporal fidelity of the Ca 2+ signaling and activation of downstream effects.

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“…Subtypespecific effects on RyR channels have been reported with several proteins, e.g. homer (61,62), glutathione transferases (63), and peptides corresponding to parts of the dihydropyridine receptor loop that display altered RyR activity depending upon the cytoplasmic [Ca 2ϩ ] (64). The opposing effects observed for the 72% identical RyR1 and RyR2 (65) suggest that the Tpx-1 Crisp domain binds to multiple regions of the ion channel on the cytoplasmic domain.…”

Section: The Tpx-1 Crisp Domain Is a Conserved Structural Element Dismentioning

confidence: 99%

The Cysteine-rich Secretory Protein Domain of Tpx-1 Is Related to Ion Channel Toxins and Regulates Ryanodine Receptor Ca2+ Signaling

Gibbs

Scanlon

Swarbrick

et al. 2006

Journal of Biological Chemistry

131

126

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The cysteine-rich secretory proteins (Crisp) are predominantly found in the mammalian male reproductive tract as well as in the venom of reptiles. Crisps are two domain proteins with a structurally similar yet evolutionary diverse N-terminal domain and a characteristic cysteine-rich C-terminal domain, which we refer to as the Crisp domain. We presented the NMR solution structure of the Crisp domain of mouse Tpx-1, and we showed that it contains two subdomains, one of which has a similar fold to the ion channel regulators BgK and ShK. Furthermore, we have demonstrated for the first time that the ion channel regulatory activity of Crisp proteins is attributed to the Crisp domain. Specifically, the Tpx-1 Crisp domain inhibited cardiac ryanodine receptor (RyR) 2 with an IC 50 between 0.5 and 1.0 M and activated the skeletal RyR1 with an AC 50 between 1 and 10 M when added to the cytoplasmic domain of the receptor. This activity was nonvoltage-dependent and weakly voltage-dependent, respectively. Furthermore, the Tpx-1 Crisp domain activated both RyR forms at negative bilayer potentials and showed no effect at positive bilayer potentials when added to the luminal domain of the receptor. These data show that the Tpx-1 Crisp domain on its own can regulate ion channel activity and provide compelling evidence for a role for Tpx-1 in the regulation of Ca 2؉ fluxes observed during sperm capacitation.Tpx-1 (testis specific protein-1) was originally identified in the mouse (1) and later found in the male reproductive tract of the human, guinea pig, rat, and horse (2-5). Tpx-1 is a member of the cysteine-rich secretory proteins (Crisp) 2 that are in turn a subgroup of the CAP protein superfamily (abbreviated from Crisp, Antigen 5, and Pr-1 (6)). The CAP proteins each contain a structurally related and unique domain, the CAP domain (7)(8)(9), that at present has no clearly defined biological function, although their spatial and temporal expression suggests a function related to the regulation of the innate immune system (10, 11) and male reproductive function. The Crisp proteins have a characteristic C-terminal sequence containing 10 absolutely conserved cysteines. The Crisp domain is unique and is only observed in association with the CAP domain. Previously, there has been no biological activity attributed specifically to this domain.In mammals, there are at least four Crisp proteins, Crisp-1, Tpx-1 (or Crisp-2), Crisp-3, and Crisp-4. Crisp-1 proteins are expressed predominantly in the epididymides where they coat the surface of sperm during epididymal maturation (12) and have been implicated in sperm oocyte binding and the regulation of capacitation (13-17). Tpx-1 is expressed only in the testis and localized to specific regions in the spermatozoa, notably the acrosome of the head, the outer dense fibers, and longitudinal columns of the fibrous sheath in the sperm tail and the connecting piece of the neck (3, 18). Transfection experiments have also suggested that Tpx-1 is involved in adhesion between germ cells and Sertoli...

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Vesl/Homer proteins regulate ryanodine receptor type 2 function and intracellular calcium signaling

Cited by 65 publications

References 30 publications

Homer/Vesl Proteins and Their Roles in CNS Neurons

Homer/Vesl Proteins and Their Roles in CNS Neurons

Homer proteins in Ca2+ signaling by excitable and non-excitable cells

The Cysteine-rich Secretory Protein Domain of Tpx-1 Is Related to Ion Channel Toxins and Regulates Ryanodine Receptor Ca2+ Signaling

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