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Poster Presentations 1P-002 Moderate Binding Affinity of the Na+/H+ Exchanger NHE1 for Calcineurin Is Critical for Downstream NFAT Signaling

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Poster Presentations 1P-002 Moderate Binding Affinity of the Na+/H+ Exchanger NHE1 for Calcineurin Is Critical for Downstream NFAT Signaling Poster Presentations 1P-002 Moderate binding affinity of the Na+/H+ exchanger NHE1 for calcineurin is critical for downstream NFAT signaling. Hisamitsu, Takashi; Wakabayashi, Shigeo(Dep. of Mol. Physiol., Natl. Cer. Cardiovas. Ctr, Osaka, Japan) Calcineurin (CaN), a Ca2+-dependent phosphatase, is a key molecule to govern pathological cardiac hypertrophy. CaN dephosphorylates a downstream transcription factor NFAT, which in turn induces hyper- trophic gene expression. However, the mechanism of CaN regulation Poster Presentations is unclear, because CaN is not activated by increase in cytosolic Ca2+ concentration caused by the excitation-contraction coupling in cardio- Ionic Channel, Receptor (1) myocytes. CaN has been hypothesized to be efficiently regulated via the interaction with plasma membrane Ca2+-handling proteins in the local vicinity. Recently, we have found that a pH-regulating transport- er NHE1 activated the CaN-NFAT signaling, leading to cardiomyocyte hypertrophy via direct binding of CaN to the 6-residues motif (PVIT- ID) in the cytosolic domain of NHE1. We hypothesized that local pH increase produced by NHE1 enhanced the activity of CaN bound to NHE1 via sensitizing Ca2+. However, it is unknown how CaN signal is transmitted from NHE1 to NFAT. In this study, we performed the detailed mutagenesis study for CaN binding site of NHE1. Substitution of the PVITID sequence with either high (PVIVIT) or low affinity sequence (PVIAVN) both abolished the CaN-NFAT signaling. Ala- nine-scanning mutagenesis revealed that the original NHE1 sequence was the best for signal amplification, suggesting that the balanced affinity between NHE1 and CaN is critical for the efficient signaling. We consider that such moderate interaction is important for removal of CaN from NHE1 and rebinding to downstream target NFAT after NHE1-dependent activation. No COI. 1P-001 1P-003 Quercetin diminishes the cAMP-stimulated Cl- secre- Stabilizing effects of G protein on the active confor- tion by blocking Na+,K+ -ATPase in epithelial cells mation of the adenosine receptor type 1a differ de- Sun, hongxin1; Niisato, Naomi1,3; Marunaka, Yoshinori1,2,3(1>_ pending on the type of G protein +;_)_>5,>_+;_)_>53Heian ( ) Tateyama, Michihiro; Kubo, Yoshihiro Div. Biophysics & Neurobiol., Dept. 0+;_>5 _>_86F0?05) Epithelial Cl- secretion plays an important role in production of driving We recently reported that the stabilizing effects of G protein binding force for water movement. The aim of the present study was to inves- on the stabilization of the active conformation of the receptor differ tigate the action of quercetin, a flavonoid, on Cl- secretion in epithelial depending on the type of receptors. In the present study, we aimed A6 cells. Quercetin stimulated epithelial Cl- secretion under basal at investigating the effects of different types of G protein on the active conditions, but diminished it under cAMP-stimulated conditions via conformation of the Gi/o-coupled adenosine type 1a receptor (A1aR), modification of activity of Na+-K+-2Cl- cotransporter (NKCC) contrib- by using a fluorescence resonance energy transfer (FRET) technique. uting to Cl- uptake across the basolateral membrane. However, we For this purpose, examined Gα subunits were the Gαi1, Gαo and the have no idea on mechanisms of quercetin action. As the Na+,K+-pump chimeric Gαqi5 which binds to the A1aR and stimulates Gq signaling is essentially required for production of the Na+ gradient generating pathway. YFP fused at the C-tail of the A1aR showed the agonist-in- NKCC activity, we assessed effects of quercetin on the pump by mea- duced increases in FRET from CFP attached to the Gβ1 subunit in suring the ouabain-sensitive current in apically nystatin-treated cells. the presence of the Gαi1 and Gαqi5 but not of the Gαo, suggesting that Quercetin reduced the pump current about 50%, but quercetin stim- the YFP-fused A1aR interacts with the Gαi1 and Gαqi5 but not with ulated NKCC. Based on these observations, we speculate the following the Gαo. To examine the effects of the different Gα subunits on the points. 1) Under basal conditions, the pump activity would be much active conformation of the A1aR, we made functionally intact A1aR larger than the NKCC activity. Therefore, even if quercetin inhibited FRET constructs which are fused with YFP and CFP at the third the pump, the Na+ gradient would be still kept large enough for intracellular loop and C-tail of the A1aR, respectively. The FRET con- quercetin to fully show its stimulatory action on NKCC, resulting in structs showed slight FRET decreases upon the agonist application, an increase of Cl--secretion. 2) Under forskolin-stimulated conditions, which were significantly enhanced by the Gαi1 and Gαqi5 but not by the pump activity would not be much larger than the NKCC activity. the Gαo subunits. In addition, the enhancing effect of the Gαqi5 on the Therefore, if quercetin inhibited the pump, the Na+ gradient would FRET decrease was significantly larger than that of the Gαi1. These not be kept large enough for maintenance of the forskolin-stimulated results suggested that effects of G protein binding on the stabilization activity of NKCC, resulting in a decrease of Cl--secretion. No COI. of the active conformation of the A1aR differ depending on the type of G protein. No COI. S116 -*=3+89=33:&1=**9.3,=4+=9-*=`=&7(-=+0=*=+2`=,*+.`=&,48-.2& 1P-004 1P-006 Structural rearrangements of the linker beta strands in Area-specific D1 dopamine receptor expression in P2X2 are coupled to the pore in a voltage dependent adult mouse astrocytes manner Nagatomo, Katsuhiro1; Suga, Sechiko2; Yamamoto, Yoshio3; Yamada Katsuya1(1Dept. Physiol., Hirosaki Univ. Grad. Sch. Med., Hirosaki, Keceli Batu; Kubo, Yoshihiro(National Institute for Physiological Sciences, Japan, , 3 F0?05) :0+;_:]/:05 2'_^_1_] 41_%5_^__'__6<+;_05) P2X is an extracellular ATP gated cation channel, which shows volt- 2 Dopaminergic neurons in the midbrain nucleus substantia nigra pars age dependent gating with no canonical voltage sensor. Three inter- compacta (SNc) release dopamine (DA) from their dendrites, which subunit ATP binding sites are linked to pore forming transmembrane extend deeply into the adjacent substantia nigra pars reticulata (SNr), (TM) domains by β-strands. We analyzed voltage dependent structur- consisting mostly of GABAergic neurons. Indeed, real time RT-PCR al rearrangements of the linker strands using an engineered thiol and immunohistochemistry showed diffuse expression of D1 dopamine modifiable site. (1) We observed that a double mutants of D315C&I67C receptor (D1R) in the SNr. However, most acutely dissociated GAB- (at β-14 and β-1 respectively) shows increase in current 3-6 fold by Aergic SNr neurons showed no response to DA applied in our perfo- reducing agent (DTT). Washout of DTT and application of Cd2+ in- rated patch experiments. Interestingly, examination of D1R-YFP trans- duced current decline due to the bond formation between D315C and genic mice revealed that SNr glial cells express strong D1R (i.e. YFP) I67C. This effect was absent in WT or in either single point mutants. signal in their process. In the present study, we compared D1R ex- (2) Cd2+ induced current decline was analyzed at depolarized and pression in acutely dissociated neurons and astrocytes in SNr, striatum, hyperpolarized potentials with different pulse protocols in the presence and cerebral cortex by double immunostainings. Vesicular GABA and absence of ATP. (3) Current decline by Cd2+ could not be observed transporter (VGAT)-venus mice were used as well. From these studies, in the absence of ATP, but only in presence of ATP, suggesting state we suggest area-specific D1R expression in astrocytes. No COI. dependent modification. (4) In presence of ATP, Cd2+ modification was faster in hyperpolarized conditions than in the depolarized condition, suggesting voltage dependent structural rearrangements of the beta strands linking ATP binding site to TM domains. (5) Finally we per- formed the similar analyses with a pore mutant T339S which makes the channel constitutively active at all membrane potentials. With T339S Cd2+ modification rates were similar in depolarized and hyper- polarized conditions. Overall results suggest that structural rearrange- ments of the linker domains of P2X2 are coupled to the pore in a voltage dependent manner. No COI. 1P-005 1P-007 Endothelin-1 induces contraction through endothelin N-glycosylation modulates AMPA receptor channel receptor A coupled with Gq/11 in bovine ciliary muscle properties Miyazu, Motoi; Ishii, Nobuhito; Takai, Akira(Dept. Physiol., Asahikawa Kandel, Munal Babu1; Wakazono, Yoshihiko1; Med. Univ., Asahikawa, Japan) Midorikawa, Ryosuke1; Oka, Shogo2; Takamiya, Kogo1(1%5 86;>>'>)+;>>?0 Purpose: To determine receptor type associated with the contractile >?05,%514>:: effect of endothelin-1 (ET1) on bovine ciliary muscle and investigate #))>+;>>5) the signalling mechanism involved. Methods: Isometric tension was recorded in dissected ciliary muscle The intracellular molecular mechanisms underlying the regulation of bundles, using a U-gauge transducer. Isolated myocytes were used for the AMPA receptor have been dramatically elucidated in the past few recording whole cell currents. Existence and localization of endothelin decades. In contrast, the regulation of the extracellular domain remains unclear. Here, we focused on N-glycosylation of the AMPA receptor receptors A and B (ETRA and ETRB), M3-muscarinic receptor (M3R) in the extracellular domain and tried to clarify their functions by and Gq/11α were examined by immunofluorescence microscopy. Results: ET1 (1-100 nM) produced a slowly developing contractile combining molecular biological and electrophysiological techniques. response τ( = 58 ± 15 min; n=12) in a dose-dependent manner (K=6 ± First, we examined the effects of PNGase F, which is a glycosidase 1 nM and h=1.1 ± 0.1; d.f.=15). Like contraction evoked by carbachol that cleaves the N-glycosylation site at an asparagine residue, on AMPA (CCh; 0.1‒10 µM), ET1-evoked contraction was dependent on extracel- currents in primary hippocampal cultured neurons and HEK293 cells 2+ expressing GluA1 using a whole-cell patch-clamp technique.
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