Background For prostate cancer, signaling pathways induced by over-boarding stimulation of G-prot... more Background For prostate cancer, signaling pathways induced by over-boarding stimulation of G-protein coupled receptors (GPCR) such as the endothelin, α1- and β-adrenergic, muscarinic and angiotensin 1 receptors were accused to support the carcinogenesis. However, excessive receptor stimulation by physiological receptor ligands is minimized by a control system that induces receptor sensitization and down-regulation. This system is missing when so-called “functional autoantibodies” bind to the GPCR (GPCR-AAB). If GPCR-AAB were found in patients with prostate cancer, uncontrolled GPCR stimulation could make these autoantibodies an additional supporter in prostate cancer. Methods Using the bioassay of spontaneously beating cultured rat neonatal cardiomyocytes, GPCR-AAB were identified, quantified and characterized in the serum of 25 patients (aged 56–78 years, median 70 years) with prostate cancer compared to 10 male patients (aged 48–82 years, median 64) with urinary stone disorders (c...
Investigative Ophthalmology & Visual Science, Jun 10, 2020
Purpose: Agonistic b2-adrenergic receptor autoantibodies (b2-agAAbs) were recently observed in se... more Purpose: Agonistic b2-adrenergic receptor autoantibodies (b2-agAAbs) were recently observed in sera of patients with ocular hypertension (OHT), primary (POAG), and secondary open-angle glaucoma (SOAG), yet not in healthy controls (HCs). It was the aim of the present study to investigate the presence of b2-agAAb in aqueous humor (AH) samples of OAG patients and to correlate these with the corresponding b2-agAAb serum data. Material and Methods: Thirty-nine patients (21 male, 18 female) were recruited from the Department of Ophthalmology, University of Erlangen-Nürnberg: twenty-one POAG, 18 SOAG. Aqueous humor samples were collected during minimal invasive glaucoma surgery. Serum and AH samples were analyzed for b2-agAAb by a bioassay quantifying the beating rate of cultured cardiomyocyte (cut-off: 2 U). Results: Thirty-six of 39 (92.3%) and 34 of 39 (87.2%) of OAG patients showed a b2-agAAb in their sera and AH samples, respectively. All b2-agAAb AH-positive OAG patients were also seropositive. We also observed a b2-agAAb seropositivity in 95 and 89% of patients with POAG and SOAG, respectively. Beta2-agAAbs were seen in 86% (POAG) and 78% (SOAG) of AH samples. The b2-agAAb adrenergic activity was increased in the AH of patients with POAG (6.5 ± 1.5 U) when compared with those with SOAG (4.1 ± 1.1 U; p = 0.004). Serum b2-agAAb adrenergic activity did not differ between the cohorts [POAG (4.5 ± 1.5 U); SOAG (4.6 ± 2.1 U; p=0.458)]. No correlation of the beating rates were observed between serum and AH samples for group and subgroup analyses. Conclusion: The detection of b2-agAAb in systemic and local circulations supports the hypothesis of a direct functional impact of these agAAbs on ocular G-protein coupled receptors. The high prevalence of b2-agAAb in serum and AH samples of patients with
Purpose Agonistic β2-adrenergic receptor autoantibodies (β2-agAAb) have been observed in sera of ... more Purpose Agonistic β2-adrenergic receptor autoantibodies (β2-agAAb) have been observed in sera of patients with ocular hypertension and open-angle glaucoma (OAG). They target the β2-receptors on trabecular meshwork, ciliary body and pericytes (Junemann et al. 2018; Hohberger et al. 2019). In addition to their influence on the intraocular pressure, an association to retinal microcirculation is discussed. This study aimed to investigate foveal avascular zone (FAZ) characteristics by en face OCT angiography (OCT-A) in glaucoma suspects and its relationship to β2-agAAb status in patients with OAG. Material and methods Thirty-four patients (28 OAG, 6 glaucoma suspects) underwent standardized, clinical examination including sensory testing as white-on-white perimetry (Octopus G1, mean defect, MD) and structural measures as retinal nerve fibre layer (RNFL) thickness, neuroretinal rim width (BMO-MRW), retinal ganglion cell layer (RGCL) thickness, and inner nuclear layer (INL) thickness with ...
PurposeAgonistic β2-adrenergic receptor autoantibodies (β2-agAAbs) were recently observed in sera... more PurposeAgonistic β2-adrenergic receptor autoantibodies (β2-agAAbs) were recently observed in sera of patients with ocular hypertension (OHT), primary (POAG), and secondary open-angle glaucoma (SOAG), yet not in healthy controls (HCs). It was the aim of the present study to investigate the presence of β2-agAAb in aqueous humor (AH) samples of OAG patients and to correlate these with the corresponding β2-agAAb serum data.Material and MethodsThirty-nine patients (21 male, 18 female) were recruited from the Department of Ophthalmology, University of Erlangen-Nürnberg: twenty-one POAG, 18 SOAG. Aqueous humor samples were collected during minimal invasive glaucoma surgery. Serum and AH samples were analyzed for β2-agAAb by a bioassay quantifying the beating rate of cultured cardiomyocyte (cut-off: 2 U).ResultsThirty-six of 39 (92.3%) and 34 of 39 (87.2%) of OAG patients showed a β2-agAAb in their sera and AH samples, respectively. All β2-agAAb AH-positive OAG patients were also seropositi...
American Journal of Physiology-heart and Circulatory Physiology, Oct 1, 2013
Recent data indicate the brain angiotensin-converting enzyme/ANG II/AT 1 receptor axis enhances e... more Recent data indicate the brain angiotensin-converting enzyme/ANG II/AT 1 receptor axis enhances emotional stress responses. In this study, we investigated whether its counterregulatory axis, the angiotensin-converting enzyme 2 (ACE2)/ ANG-(1-7)/Mas axis, attenuate the cardiovascular responses to acute emotional stress. In conscious male Wistar rats, the tachycardia induced by acute stress (air jet 10 l/min) was attenuated by intravenous injection of ANG-(1-7) [⌬ heart rate (HR): saline 136 Ϯ 22 vs. ANG-(1-7) 61 Ϯ 25 beats/min; P Ͻ 0.05]. Peripheral injection of the ACE2 activator compound, XNT, abolished the tachycardia induced by acute stress. We found a similar effect after intracerebroventricular injections of either ANG-(1-7) or XNT. Under urethane anesthesia, the tachycardia evoked by the beta-adrenergic agonist was markedly reduced by ANG-(1-7) [⌬HR: saline 100 Ϯ 16 vs. ANG-(1-7) 18 Ϯ 15 beats/min; P Ͻ 0.05]. The increase in renal sympathetic nerve activity (RSNA) evoked by isoproterenol was also abolished after the treatment with ANG-(1-7) [⌬RSNA: saline 39% vs. ANG-(1-7) Ϫ23%; P Ͻ 0.05]. The tachycardia evoked by disinhibition of dorsomedial hypothalamus neurons, a key nucleus for the cardiovascular response to emotional stress, was reduced by ϳ45% after intravenous injection of ANG-(1-7). In cardiomyocyte, the incubation with ANG-(1-7) (1 M) markedly attenuated the increases in beating rate induced by isoproterenol. Our data show that activation of the ACE2/ANG-(1-7)/Mas axis attenuates stress-induced tachycardia. This effect might be either via the central nervous system reducing anxiety level and/or interfering with the positive chronotropy mediated by activation of cardiac  adrenergic receptors. Therefore, ANG-(1-7) might contribute to reduce the sympathetic load to the heart during situations of emotional stress, reducing the cardiovascular risk. angiotensin; cardiovascular; stress RECENT LITERATURE subdivides the renin-angiotensin system (RAS) into two distinct counterregulatory axes (21, 22, 59). The classical axis involves the formation of angiotensin (ANG)
β1-adrenergic receptors (β1ARs) mediate catecholamine actions in cardiomyocytes by coupling to bo... more β1-adrenergic receptors (β1ARs) mediate catecholamine actions in cardiomyocytes by coupling to both Gs/cAMP-dependent and Gs-independent/growth-regulatory pathways. Structural studies of the β1AR define ligand-binding sites in the transmembrane helices and effector docking sites at the intracellular surface of the β1AR, but the extracellular N-terminus, which is a target for post-translational modifications, typically is ignored. This study identifies β1AR N-terminal O-glycosylation at Ser37/Ser41 as a mechanism that prevents β1AR N-terminal cleavage. We used an adenoviral overexpression strategy to show that both full-length/glycosylated β1ARs and N-terminally truncated glycosylation-defective β1ARs couple to cAMP and ERK-MAPK signaling pathways in cardiomyocytes. However, a glycosylation defect that results in N-terminal truncation stabilizes β1ARs in a conformation that is biased toward the cAMP pathway. The identification of O-glycosylation and N-terminal cleavage as novel struc...
Background: Agonistic AT 1 receptor autoantibodies (AT 1-AA) have been described in hypertensive ... more Background: Agonistic AT 1 receptor autoantibodies (AT 1-AA) have been described in hypertensive and preeclamptic patients. Furthermore, monocytes are activated in hypertensive patients. We investigated and compared the ability of angiotensin II (Ang II) and AT 1-AA to stimulate monocytes from hypertensive and normotensive persons. The adhesiveness of the monocytes to endothelial cell layers, tissue factor expression, and chemiluminescence were determined. Methods: Blood samples were obtained from 17 patients with essential hypertension and from 20 normotensive subjects. Peripheral blood monocytes were isolated by Dynabeads and used in adhesion experiments. Adherence assays, Western blotting, and reactive oxygen species release by chemiluminescence were done. Results: Monocyte adhesion to human aortic or umbilical vein endothelial cell layers was significantly higher after stimulation with AT 1-AA, compared to Ang II or no stimulation. The effect was blocked with tissue factor antibody or epitope peptide preincubation. Eposartan was partially effective in blocking the effects. Western blotting after AT 1-AA or Ang II stimulation showed that the monocytes expressed tissue factor. The AT 1-AA and Ang II induced significantly higher chemiluminescence in monocytes from hypertensive than control subjects. Endothelial cells, on the other hand, showed much less chemiluminescence. Conclusions: These data show that monocytes can be stimulated by AT 1-AA and Ang II to adhere, produce tissue factor, and probably reactive oxygen species. They underscore the importance of monocyte activation in hypertensive patients. The relevance of AT 1-AA in hypertension will require further studies.
In primary cultures of neonatal rat heart cells we found a linear correlation between the number ... more In primary cultures of neonatal rat heart cells we found a linear correlation between the number of L-type calcium channelspecific dihydropyridine (DHP) binding sites and spontaneous beating frequency (v). Formation of glycoproteins in tissue culture was suppressed by different inhibitors ofN-glycosylation. This inhibition alters to a different extent the binding of the DHP ligand (+)-[methyPH]PN 200-110 and v. The most severe but reversible effect occurs at 6 Ilg/ml tunicamycin (B ~ 45% and v ~ 6%, resp., of control), a slight increase in B at 0.1-0.5 mM castano spermine and 0.05-2.5 mM deo;Ymannojirimycin. The other inhibitors gave no significant alterati~ns of B .
Background: The -adrenergic receptors of the myocardium play an important role in the regulation... more Background: The -adrenergic receptors of the myocardium play an important role in the regulation of heart function. The -adrenergic receptors belong to the family of G-protein coupled receptors. Three subtypes have been distinguished (1-, 2-, and 3-adrenoceptors). The receptors consist of seven membrane-spanning domains, three intra-and three extracellular loops, one extracellular N-terminal domain, and one intracellular C-terminal tail. Pathophysiology: Stimulation of -adrenergic receptors by catecholamines is realized via the -adrenoceptor-adenylylcyclase-protein kinase A cascade. The second messenger is the cyclic AMP (cAMP). Stimulation of the cascade caused an accumulation of the second messenger cAMP and activated via the cAMP the cAMP dependent protein kinase A (PKA) The PKA phosphorylated, beside other cell proteins, the -adrenergic receptors. A phosphorylation of the -adrenergic receptors caused-with exception of the 3-adrenoceptor-an uncoupling and desensitisation of the receptors. Phosphorylation via the G-protein receptor kinase (GRK or ARK) also caused uncoupling and reduced the -adrenergic responsiveness. The uncoupling of the receptor is the prerequisite for receptor internalisation. In the process of internalisation the receptor shifted from the sarcolemma membrane into cytosolic compartments. Chronic -adrenergic stimulation caused a down-Die-adrenergen Rezeptoren Charakterisierung: Die -adrenergen Rezeptoren des Herzens spielen in der Regulation der Herzfunktion eine entscheidende Rolle. Diese Rezeptoren gehören zur Familie der G-Proteingekoppelten Rezeptoren und lassen sich in drei Subtypen (1-, 2und 3-Adrenozeptor) unterteilen. Die Rezeptoren bestehen aus sieben Domänen, welche die Zellmembran durchspannen, aus jeweils drei intra-und extrazellulären Schleifen, einem extrazellulären N-Terminus und einem intrazellulären C-Terminus. Pathophysiologie: Bei einer Stimulierung dieser Rezeptoren durch Katecholamine wird das Signal über die -Adrenozep-tor-Adenylylcyclase-Proteinkinase A-Kaskade in die Zelle vermittelt. Der "Second Messenger" ist das zyklische AMP (cAMP). Eine Stimulierung der Kaskade führt zu Akkumulation des cAMP und zu einer cAMP-vermittelten Aktivierung der Proteinkinase A (PKA). Die PKA phosphoryliert neben verschiedensten Zellproteinen auch -adrenerge Rezeptoren. Eine Phosphorylierung der -Adrenozeptoren führt, mit Ausnahme des 3-Rezeptors, zu einer Entkopplung und zu einer Desensibilisierung der Rezeptoren. Eine Phosphorylierung durch die G-Protein-Rezeptorkinase (GRK bzw. -ARK) entkoppelt ebenfalls die Rezeptoren und führt zu einer Verminderung der 
Background For prostate cancer, signaling pathways induced by over-boarding stimulation of G-prot... more Background For prostate cancer, signaling pathways induced by over-boarding stimulation of G-protein coupled receptors (GPCR) such as the endothelin, α1- and β-adrenergic, muscarinic and angiotensin 1 receptors were accused to support the carcinogenesis. However, excessive receptor stimulation by physiological receptor ligands is minimized by a control system that induces receptor sensitization and down-regulation. This system is missing when so-called “functional autoantibodies” bind to the GPCR (GPCR-AAB). If GPCR-AAB were found in patients with prostate cancer, uncontrolled GPCR stimulation could make these autoantibodies an additional supporter in prostate cancer. Methods Using the bioassay of spontaneously beating cultured rat neonatal cardiomyocytes, GPCR-AAB were identified, quantified and characterized in the serum of 25 patients (aged 56–78 years, median 70 years) with prostate cancer compared to 10 male patients (aged 48–82 years, median 64) with urinary stone disorders (c...
Investigative Ophthalmology & Visual Science, Jun 10, 2020
Purpose: Agonistic b2-adrenergic receptor autoantibodies (b2-agAAbs) were recently observed in se... more Purpose: Agonistic b2-adrenergic receptor autoantibodies (b2-agAAbs) were recently observed in sera of patients with ocular hypertension (OHT), primary (POAG), and secondary open-angle glaucoma (SOAG), yet not in healthy controls (HCs). It was the aim of the present study to investigate the presence of b2-agAAb in aqueous humor (AH) samples of OAG patients and to correlate these with the corresponding b2-agAAb serum data. Material and Methods: Thirty-nine patients (21 male, 18 female) were recruited from the Department of Ophthalmology, University of Erlangen-Nürnberg: twenty-one POAG, 18 SOAG. Aqueous humor samples were collected during minimal invasive glaucoma surgery. Serum and AH samples were analyzed for b2-agAAb by a bioassay quantifying the beating rate of cultured cardiomyocyte (cut-off: 2 U). Results: Thirty-six of 39 (92.3%) and 34 of 39 (87.2%) of OAG patients showed a b2-agAAb in their sera and AH samples, respectively. All b2-agAAb AH-positive OAG patients were also seropositive. We also observed a b2-agAAb seropositivity in 95 and 89% of patients with POAG and SOAG, respectively. Beta2-agAAbs were seen in 86% (POAG) and 78% (SOAG) of AH samples. The b2-agAAb adrenergic activity was increased in the AH of patients with POAG (6.5 ± 1.5 U) when compared with those with SOAG (4.1 ± 1.1 U; p = 0.004). Serum b2-agAAb adrenergic activity did not differ between the cohorts [POAG (4.5 ± 1.5 U); SOAG (4.6 ± 2.1 U; p=0.458)]. No correlation of the beating rates were observed between serum and AH samples for group and subgroup analyses. Conclusion: The detection of b2-agAAb in systemic and local circulations supports the hypothesis of a direct functional impact of these agAAbs on ocular G-protein coupled receptors. The high prevalence of b2-agAAb in serum and AH samples of patients with
Purpose Agonistic β2-adrenergic receptor autoantibodies (β2-agAAb) have been observed in sera of ... more Purpose Agonistic β2-adrenergic receptor autoantibodies (β2-agAAb) have been observed in sera of patients with ocular hypertension and open-angle glaucoma (OAG). They target the β2-receptors on trabecular meshwork, ciliary body and pericytes (Junemann et al. 2018; Hohberger et al. 2019). In addition to their influence on the intraocular pressure, an association to retinal microcirculation is discussed. This study aimed to investigate foveal avascular zone (FAZ) characteristics by en face OCT angiography (OCT-A) in glaucoma suspects and its relationship to β2-agAAb status in patients with OAG. Material and methods Thirty-four patients (28 OAG, 6 glaucoma suspects) underwent standardized, clinical examination including sensory testing as white-on-white perimetry (Octopus G1, mean defect, MD) and structural measures as retinal nerve fibre layer (RNFL) thickness, neuroretinal rim width (BMO-MRW), retinal ganglion cell layer (RGCL) thickness, and inner nuclear layer (INL) thickness with ...
PurposeAgonistic β2-adrenergic receptor autoantibodies (β2-agAAbs) were recently observed in sera... more PurposeAgonistic β2-adrenergic receptor autoantibodies (β2-agAAbs) were recently observed in sera of patients with ocular hypertension (OHT), primary (POAG), and secondary open-angle glaucoma (SOAG), yet not in healthy controls (HCs). It was the aim of the present study to investigate the presence of β2-agAAb in aqueous humor (AH) samples of OAG patients and to correlate these with the corresponding β2-agAAb serum data.Material and MethodsThirty-nine patients (21 male, 18 female) were recruited from the Department of Ophthalmology, University of Erlangen-Nürnberg: twenty-one POAG, 18 SOAG. Aqueous humor samples were collected during minimal invasive glaucoma surgery. Serum and AH samples were analyzed for β2-agAAb by a bioassay quantifying the beating rate of cultured cardiomyocyte (cut-off: 2 U).ResultsThirty-six of 39 (92.3%) and 34 of 39 (87.2%) of OAG patients showed a β2-agAAb in their sera and AH samples, respectively. All β2-agAAb AH-positive OAG patients were also seropositi...
American Journal of Physiology-heart and Circulatory Physiology, Oct 1, 2013
Recent data indicate the brain angiotensin-converting enzyme/ANG II/AT 1 receptor axis enhances e... more Recent data indicate the brain angiotensin-converting enzyme/ANG II/AT 1 receptor axis enhances emotional stress responses. In this study, we investigated whether its counterregulatory axis, the angiotensin-converting enzyme 2 (ACE2)/ ANG-(1-7)/Mas axis, attenuate the cardiovascular responses to acute emotional stress. In conscious male Wistar rats, the tachycardia induced by acute stress (air jet 10 l/min) was attenuated by intravenous injection of ANG-(1-7) [⌬ heart rate (HR): saline 136 Ϯ 22 vs. ANG-(1-7) 61 Ϯ 25 beats/min; P Ͻ 0.05]. Peripheral injection of the ACE2 activator compound, XNT, abolished the tachycardia induced by acute stress. We found a similar effect after intracerebroventricular injections of either ANG-(1-7) or XNT. Under urethane anesthesia, the tachycardia evoked by the beta-adrenergic agonist was markedly reduced by ANG-(1-7) [⌬HR: saline 100 Ϯ 16 vs. ANG-(1-7) 18 Ϯ 15 beats/min; P Ͻ 0.05]. The increase in renal sympathetic nerve activity (RSNA) evoked by isoproterenol was also abolished after the treatment with ANG-(1-7) [⌬RSNA: saline 39% vs. ANG-(1-7) Ϫ23%; P Ͻ 0.05]. The tachycardia evoked by disinhibition of dorsomedial hypothalamus neurons, a key nucleus for the cardiovascular response to emotional stress, was reduced by ϳ45% after intravenous injection of ANG-(1-7). In cardiomyocyte, the incubation with ANG-(1-7) (1 M) markedly attenuated the increases in beating rate induced by isoproterenol. Our data show that activation of the ACE2/ANG-(1-7)/Mas axis attenuates stress-induced tachycardia. This effect might be either via the central nervous system reducing anxiety level and/or interfering with the positive chronotropy mediated by activation of cardiac  adrenergic receptors. Therefore, ANG-(1-7) might contribute to reduce the sympathetic load to the heart during situations of emotional stress, reducing the cardiovascular risk. angiotensin; cardiovascular; stress RECENT LITERATURE subdivides the renin-angiotensin system (RAS) into two distinct counterregulatory axes (21, 22, 59). The classical axis involves the formation of angiotensin (ANG)
β1-adrenergic receptors (β1ARs) mediate catecholamine actions in cardiomyocytes by coupling to bo... more β1-adrenergic receptors (β1ARs) mediate catecholamine actions in cardiomyocytes by coupling to both Gs/cAMP-dependent and Gs-independent/growth-regulatory pathways. Structural studies of the β1AR define ligand-binding sites in the transmembrane helices and effector docking sites at the intracellular surface of the β1AR, but the extracellular N-terminus, which is a target for post-translational modifications, typically is ignored. This study identifies β1AR N-terminal O-glycosylation at Ser37/Ser41 as a mechanism that prevents β1AR N-terminal cleavage. We used an adenoviral overexpression strategy to show that both full-length/glycosylated β1ARs and N-terminally truncated glycosylation-defective β1ARs couple to cAMP and ERK-MAPK signaling pathways in cardiomyocytes. However, a glycosylation defect that results in N-terminal truncation stabilizes β1ARs in a conformation that is biased toward the cAMP pathway. The identification of O-glycosylation and N-terminal cleavage as novel struc...
Background: Agonistic AT 1 receptor autoantibodies (AT 1-AA) have been described in hypertensive ... more Background: Agonistic AT 1 receptor autoantibodies (AT 1-AA) have been described in hypertensive and preeclamptic patients. Furthermore, monocytes are activated in hypertensive patients. We investigated and compared the ability of angiotensin II (Ang II) and AT 1-AA to stimulate monocytes from hypertensive and normotensive persons. The adhesiveness of the monocytes to endothelial cell layers, tissue factor expression, and chemiluminescence were determined. Methods: Blood samples were obtained from 17 patients with essential hypertension and from 20 normotensive subjects. Peripheral blood monocytes were isolated by Dynabeads and used in adhesion experiments. Adherence assays, Western blotting, and reactive oxygen species release by chemiluminescence were done. Results: Monocyte adhesion to human aortic or umbilical vein endothelial cell layers was significantly higher after stimulation with AT 1-AA, compared to Ang II or no stimulation. The effect was blocked with tissue factor antibody or epitope peptide preincubation. Eposartan was partially effective in blocking the effects. Western blotting after AT 1-AA or Ang II stimulation showed that the monocytes expressed tissue factor. The AT 1-AA and Ang II induced significantly higher chemiluminescence in monocytes from hypertensive than control subjects. Endothelial cells, on the other hand, showed much less chemiluminescence. Conclusions: These data show that monocytes can be stimulated by AT 1-AA and Ang II to adhere, produce tissue factor, and probably reactive oxygen species. They underscore the importance of monocyte activation in hypertensive patients. The relevance of AT 1-AA in hypertension will require further studies.
In primary cultures of neonatal rat heart cells we found a linear correlation between the number ... more In primary cultures of neonatal rat heart cells we found a linear correlation between the number of L-type calcium channelspecific dihydropyridine (DHP) binding sites and spontaneous beating frequency (v). Formation of glycoproteins in tissue culture was suppressed by different inhibitors ofN-glycosylation. This inhibition alters to a different extent the binding of the DHP ligand (+)-[methyPH]PN 200-110 and v. The most severe but reversible effect occurs at 6 Ilg/ml tunicamycin (B ~ 45% and v ~ 6%, resp., of control), a slight increase in B at 0.1-0.5 mM castano spermine and 0.05-2.5 mM deo;Ymannojirimycin. The other inhibitors gave no significant alterati~ns of B .
Background: The -adrenergic receptors of the myocardium play an important role in the regulation... more Background: The -adrenergic receptors of the myocardium play an important role in the regulation of heart function. The -adrenergic receptors belong to the family of G-protein coupled receptors. Three subtypes have been distinguished (1-, 2-, and 3-adrenoceptors). The receptors consist of seven membrane-spanning domains, three intra-and three extracellular loops, one extracellular N-terminal domain, and one intracellular C-terminal tail. Pathophysiology: Stimulation of -adrenergic receptors by catecholamines is realized via the -adrenoceptor-adenylylcyclase-protein kinase A cascade. The second messenger is the cyclic AMP (cAMP). Stimulation of the cascade caused an accumulation of the second messenger cAMP and activated via the cAMP the cAMP dependent protein kinase A (PKA) The PKA phosphorylated, beside other cell proteins, the -adrenergic receptors. A phosphorylation of the -adrenergic receptors caused-with exception of the 3-adrenoceptor-an uncoupling and desensitisation of the receptors. Phosphorylation via the G-protein receptor kinase (GRK or ARK) also caused uncoupling and reduced the -adrenergic responsiveness. The uncoupling of the receptor is the prerequisite for receptor internalisation. In the process of internalisation the receptor shifted from the sarcolemma membrane into cytosolic compartments. Chronic -adrenergic stimulation caused a down-Die-adrenergen Rezeptoren Charakterisierung: Die -adrenergen Rezeptoren des Herzens spielen in der Regulation der Herzfunktion eine entscheidende Rolle. Diese Rezeptoren gehören zur Familie der G-Proteingekoppelten Rezeptoren und lassen sich in drei Subtypen (1-, 2und 3-Adrenozeptor) unterteilen. Die Rezeptoren bestehen aus sieben Domänen, welche die Zellmembran durchspannen, aus jeweils drei intra-und extrazellulären Schleifen, einem extrazellulären N-Terminus und einem intrazellulären C-Terminus. Pathophysiologie: Bei einer Stimulierung dieser Rezeptoren durch Katecholamine wird das Signal über die -Adrenozep-tor-Adenylylcyclase-Proteinkinase A-Kaskade in die Zelle vermittelt. Der "Second Messenger" ist das zyklische AMP (cAMP). Eine Stimulierung der Kaskade führt zu Akkumulation des cAMP und zu einer cAMP-vermittelten Aktivierung der Proteinkinase A (PKA). Die PKA phosphoryliert neben verschiedensten Zellproteinen auch -adrenerge Rezeptoren. Eine Phosphorylierung der -Adrenozeptoren führt, mit Ausnahme des 3-Rezeptors, zu einer Entkopplung und zu einer Desensibilisierung der Rezeptoren. Eine Phosphorylierung durch die G-Protein-Rezeptorkinase (GRK bzw. -ARK) entkoppelt ebenfalls die Rezeptoren und führt zu einer Verminderung der 
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Papers by Gerd Wallukat