Figure 1.

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 I_Kv and I_A, and stimulates I_Ca resulting in increased neuronal firing rate via PLC-mediated activation of PKC. PLC also activates CaMKII, which contributes to I_Kv 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; I_A, transient A type K⁺ current; I_Ca, total Ca²⁺ current; I_Kv, 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.