α 1B 1B -Adrenoceptor phosphorylation. Adrenoceptor phosphorylation. Roles(s) of autocrine/ paracrine Roles(s) of autocrine/ paracrine Communication? Communication? J. Adolfo García J. Adolfo García- -Sáinz Sáinz Instituto de Fisiología Celula Instituto de Fisiología Celula UNAM UNAM
α 1D α 2C β 3 α 1B α 2B β 2 α 1A α 2A β 1 1 α 2 α β ADRENERGIC RECEPTORS
Extracellular S N S S T Q N P G T F N A D K L E G W Q A P A S T N H G T D L D P N M T Amino-terminus L P Q L D D D K E C A 293 � E or I V W V L G R G V T N Constitutive activity Y I S T L K P P R P T G F A A E C L P F D I E S V G V E L D I W E K W P F Y L S G A V F A L V L G T A S F A A V D G L L P A L F S L P L K V V F Plasma A F I P L V V L C G I S S L G I F F W L G I V T S L F A I T F S L C T A S S F Y I P L W C Y F N S membrane L V W V G N L L D I L S P L A L I F C L N V S L L I L V I A I A L L C A I V I L V M G V V P I I Y A L I L S V N V I S I D M Y C I G L P C S T S K A F A R R V K Y K C N R H L R T P T N Y E F K R A G α 14 coupling sites Y A R I A R G I K T V F VA R L E A G V M K T T K N V K R M E D 142 � A or T Y S L Q Y P T L E R M R I S F N K S H I R L T L E K Constitutive activity S N L F S G α q coupling site H G ED K C V K L F T L Q S S T K A K G H N P R S S I A C R S Q S S K R S R E L G G R T W P R Y T Y A C A G L R R R R R R R R G Phosphorylation sites D S PKC � S L D D S G S C M S G S Q R T L P S A S P S P G Y L G R G A Q P P L E L GRK � S C A E G L L K F T F L P G S D L R G R R G P P E P L S L L A G S K W E P Y P E S P G T E G D A S N G G C D A T T D L A N G Q P G F K S N M P L A P G H Carboxyl-terminus Intracellular F
Desensitization Desensitization 100 EFFECT 75 50 25 0 0 1 2 3 4 5 [DRUG]
Homologous desensitization Homologous desensitization
Agonist Agonist PI3K PL-C PDK-1 PKC ? DG Heterologous desensitization Heterologous desensitization
Does LPA induce Does LPA induce α 1B 1B -AR phosphorylation? AR phosphorylation? How does it take place? How does it take place?
LPA-R AC α PLC γ γ β G i AMPc IP3 ions DG PI3K
PTX μ g/ml LOG [ LPA ] M 0.0 - 10 - 9 - 8 - 7 - 6 - 5 0.3 B NE LPA TPA α 1b -AR PHOSPHORYLATION CONTROL PT X 250 α 1b -AR PHOSPHORYLATION 300 (% OF BASAL) 200 (% OF BASAL) 200 150 C ONT STAU * 100 GEN 100 -10 -8 -6 -4 W OR T NE LPA TPA LOG [ LPA ] M B NE L PA NE LP A 300 α 1b -AR PHOSPHORYLATION (% OF BASAL) 200 * * 100 CONT STAU GEN WORT
α 1B -AR LPA-R α PDK1 γ γ β ? PI3K G i ? PKC
EGF-R α 1B -AR HB-EGF LPA-R MP α γ γ β PDK PI3K G i PKC
Is the EFG receptor role general ? Is the EFG receptor role general ?
NA +AG α 1B -Adrenoceptor Phosphorylation NA (% of basal) - Log [Noradrenaline] M 100 125 150 175 B -9 -9 PMA +AG PMA -8 α 1B -Adrenoceptor Phosphorylation -7 (% of basal) -7 100 150 200 250 -6 -5 B -5 - Log [PMA] M -9 -9 α 1B -Adrenoceptor Phosphorylation Et-1 +AG -8 (% of basal) -8 Et-1 -7 100 125 150 175 200 225 -7 - Log [Endothelin-1] M -6 -6 B -10 -9 -10 -9 -8 -8 -7 -7
α 1B -Adrenoceptor Phosphorylation (% of basal) 100 150 200 EGF receptor autophosphorylation Basal Basal Basal Et Et Et-1 * Et +AG ** +AG + BB-94 +BB ** +BB +aHB-EGF +WT +aHB-EGF ** EGF +WT ** EGF + BB -94
α 1B -Adrenoceptor Phosphorylation (% of basal) EGF receptor autophosphorylation 100 150 200 Basal Basal Basal Basal + BB-94 * NA NA NA +AG ** ** ** +AG NA +BB +BB + BB-94 +aHB-EGF +WT +aHB-EGF EGF +WT EGF + BB-94
Model for α 1B Model for 1B -AR homologous desensitization AR homologous desensitization α 1B -AR HB-EGF EGF-R MP DG α γ γ β PI3K GRK PDK PKC
Does TRK activation induce Does TRK activation induce α 1D 1D -AR phosphorylation and AR phosphorylation and desensitization? desensitization?
Δ [Ca 2+ ]i [nM] 2000 NA 1000 0 0 25 50 75 100 Time (seconds) + INS Δ [Ca 2+ ]i [nM] + IGF-I Δ [Ca 2+ ]i [nM] 2000 NA 2000 NA 1000 1000 0 0 0 25 50 75 100 0 25 50 75 100 Time (seconds) Time (seconds) + EGF Δ [Ca 2+ ]i [nM] + PDGF Δ [Ca 2+ ]i [nM] NA 2000 NA 2000 1000 1000 0 0 0 25 50 75 100 0 25 50 75 100 Time (seconds) Time (seconds)
IGF- I 0 1 3 10 30 100 0 0.01 0.1 1.0 10 100 α 1D -Adrenoceptor phosphorylation α 1D -Adrenoceptor phosphorylation 250 250 ( % of basal) ( % of basal) 200 200 150 150 100 100 0 1 10 100 0 0.01 1.0 100 Insulin (ng/ml) IGF -I (ng/ml) 0 0.01 0.1 1.0 10 100 0 0.01 0.1 1.0 10 100 α 1D -Adrenoceptor phosphorylation α 1D -Adrenoceptor phosphorylation 250 250 ( % of basal) ( % of basal) 200 200 150 150 100 100 0 0.01 1.0 100 0 0.01 1.0 100 PDGF (ng/ml) EGF (ng/ml)
Patricia Casas Patricia Casas- -González González M. Teresa Romero M. Teresa Romero- -Ávila Ávila Tzindilú Molina Tzindilú Molina- -Muñoz Muñoz Ekaterina Rodríguez Ekaterina Rodríguez Ekaterina Kalashnikova Ekaterina Kalashnikova Erika Calvo Erika Calvo Guadalupe Reyes Guadalupe Reyes- -Cruz Cruz- - CINVESTAV CINVESTAV
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