Functional responses to angiotensin Ⅱ (AT-Ⅱ) were determined in aortic vascular smooth muscle cells (VSMCs) from experimental cirrhotic rats. Our data showed that AT-Ⅱ-stimulated extracellular acidification rate (E...Functional responses to angiotensin Ⅱ (AT-Ⅱ) were determined in aortic vascular smooth muscle cells (VSMCs) from experimental cirrhotic rats. Our data showed that AT-Ⅱ-stimulated extracellular acidification rate (ECAR), which was measured by Cytosensor microphysiometry, was significantly reduced in the aortic VSMCs from the cirrhotic rats as compared to those from the control animals. The ability of AT-Ⅱ to promote formation of inositol phosphates, the second messenger produced by the activation of Gq-coupled receptors, was also considerably suppressed in the cirrhotic VSMCs. Furthermore, the maximal p42/44 MAPK phosphorylation stimulated by AT-Ⅱ was significantly reduced in the cirrhotic VSMCs in contrast to that in the normal VSMCs. Taken together, our data clearly demonstrated that the functional responses to AT-Ⅱ was severely suppressed in aortic VSMCs in cirrhosis, indicating the impairment of general Gq-coupled receptor signaling and subsequent biological function in the cirrhotic VSMCs.展开更多
Dysregulated GABAergic inhibition in the amygdala has long been implicated in stress-related neuropsychiatric disorders.However,the molecular and circuit mechanisms underlying the dysregulation remain elusive.Here,by ...Dysregulated GABAergic inhibition in the amygdala has long been implicated in stress-related neuropsychiatric disorders.However,the molecular and circuit mechanisms underlying the dysregulation remain elusive.Here,by using a mouse model of chronic social defeat stress(CSDS),we observed that the dysregulation varied drastically across individual projection neurons(PNs)in the basolateral amygdala(BLA),one of the kernel amygdala subregions critical for stress coping.While persistently reducing the extrasynaptic GABAAreceptor(GABA_(A)R)-mediated tonic current in the BLA PNs projecting to the ventral hippocampus(BLA→v HPC PNs),CSDS increased the current in those projecting to the anterodorsal bed nucleus of stria terminalis(BLA→adBNST PNs),suggesting projection-based dysregulation of tonic inhibition in BLA PNs by CSDS.Transcriptional and electrophysiological analysis revealed that the opposite CSDS influences were mediated by loss-and gain-of-function ofδ-containing GABA_(A)Rs(GABA_(A)(δ)Rs)in BLA→vHPC and BLA→adBNST PNs,respectively.Importantly,it was the lost inhibition in the former population but not the augmentation in the latter population that correlated with the increased anxiety-like behavior in CSDS mice.Virally mediated maintenance of GABA_(A)(δ)R currents in BLA→vHPC PNs occluded CSDS-induced anxiety-like behavior.These findings clarify the molecular substrate for the dysregulated GABAergic inhibition in amygdala circuits for stress-associated psychopathology.展开更多
文摘Functional responses to angiotensin Ⅱ (AT-Ⅱ) were determined in aortic vascular smooth muscle cells (VSMCs) from experimental cirrhotic rats. Our data showed that AT-Ⅱ-stimulated extracellular acidification rate (ECAR), which was measured by Cytosensor microphysiometry, was significantly reduced in the aortic VSMCs from the cirrhotic rats as compared to those from the control animals. The ability of AT-Ⅱ to promote formation of inositol phosphates, the second messenger produced by the activation of Gq-coupled receptors, was also considerably suppressed in the cirrhotic VSMCs. Furthermore, the maximal p42/44 MAPK phosphorylation stimulated by AT-Ⅱ was significantly reduced in the cirrhotic VSMCs in contrast to that in the normal VSMCs. Taken together, our data clearly demonstrated that the functional responses to AT-Ⅱ was severely suppressed in aortic VSMCs in cirrhosis, indicating the impairment of general Gq-coupled receptor signaling and subsequent biological function in the cirrhotic VSMCs.
基金supported by National Natural Science Foundation of China(82125010,81930032,31970953,81741759,31700916,and 81601179)Natural Science Foundation of Jiangxi Province(20172BCB22005,20192ACB20023,and 20192ACB21024)。
文摘Dysregulated GABAergic inhibition in the amygdala has long been implicated in stress-related neuropsychiatric disorders.However,the molecular and circuit mechanisms underlying the dysregulation remain elusive.Here,by using a mouse model of chronic social defeat stress(CSDS),we observed that the dysregulation varied drastically across individual projection neurons(PNs)in the basolateral amygdala(BLA),one of the kernel amygdala subregions critical for stress coping.While persistently reducing the extrasynaptic GABAAreceptor(GABA_(A)R)-mediated tonic current in the BLA PNs projecting to the ventral hippocampus(BLA→v HPC PNs),CSDS increased the current in those projecting to the anterodorsal bed nucleus of stria terminalis(BLA→adBNST PNs),suggesting projection-based dysregulation of tonic inhibition in BLA PNs by CSDS.Transcriptional and electrophysiological analysis revealed that the opposite CSDS influences were mediated by loss-and gain-of-function ofδ-containing GABA_(A)Rs(GABA_(A)(δ)Rs)in BLA→vHPC and BLA→adBNST PNs,respectively.Importantly,it was the lost inhibition in the former population but not the augmentation in the latter population that correlated with the increased anxiety-like behavior in CSDS mice.Virally mediated maintenance of GABA_(A)(δ)R currents in BLA→vHPC PNs occluded CSDS-induced anxiety-like behavior.These findings clarify the molecular substrate for the dysregulated GABAergic inhibition in amygdala circuits for stress-associated psychopathology.
