AT1 receptor signal transduction pathways that result in transcriptional NA neuromodulation (a) and increased firing rate (b) in neuronal cultures

AT1 receptor signal transduction pathways that result in transcriptional NA neuromodulation (a) and increased firing rate (b) in neuronal cultures. (a) AT1 receptor activation increases the transcription of TH, D-βH and the NAT via a PLC-dependent Ras–Raf–MAP kinase pathway. This induces Fos and Jun by increasing c-fos and c-jun gene expression. PKC and PI3K mediate FRK and JNK activity, respectively, which in turn phosphorylate Fos and Jun, resulting in transactivation of the AP1 transcription complex. Interaction of the AP1 complex with AP1 binding sites in the promotor regions of TH, D-βH and the NAT results in transcription of these genes. A PI3K–PKB/Akt pathway (highlighted in red) uniquely mediates the augmented transcriptional NA neuromodulation in SHR neurons. Increased AP1 nuclear binding in SHR neurons may be due to enhanced PI3K-mediated JNK activity, resulting in subsequent increases in Jun phosphorylation and AP1 binding. (b) AT1 receptor activation inhibits IKv and IA, and stimulates ICa resulting in increased neuronal firing rate via PLC-mediated activation of PKC. PLC also activates CaMKII, which contributes to IKv inhibition. An additional signaling pathway that utilizes PI3K (pathway highlighted in red) mediates the enhanced Ang II-induced neuronal firing response in SHR neurons. Ang, angiotensin; AP1, activating protein 1; AT1R, angiotensin type 1 receptor; [Ca2+]i, intracellular calcium; CaMKII, calcium/calmodulin-dependent protein kinase II; DAG, diacylglycerol; D-βH, dopamine β-hydroxylase; FRK, Fos-regulating kinase; IA, transient A type K+ current; ICa, total Ca2+ current; IKv, delayed rectifier K+ current; IP3, inositol 1,4,5-triphosphate; JNK, c-Jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; NA, noradrenaline; NAT, NA transporter; PI3K, phosphoinositide-3-kinase; PKB, protein kinase B; PKC, protein kinase C; PLC, phospholipase C; TH, tyrosine hydroxylase.

Publication

Brain renin–angiotensin system dysfunction in hypertension: recent advances and perspectives. (2003) Shereeni J Veerasingham, et al. Br J Pharmacol. 2003 May;139(2):191-202. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

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