Mingyan Zhu

Angiotensin At1 Receptor Signalling Pathways In Neurons

1.u2002The aim of the present article is to review the intracellular signal transduction pathways that are influenced by the peptide angiotensin (Ang) II, acting via its type 1 (AT1) receptor, in neurons.

Functional Interactions Between Neuronal AT1 and AT2 Receptors

Angiotensin II (Ang II), via the activation of the AT1 and AT2 receptors regulates electrophysiological responses of catecholaminergic neurons. This study was designed to determine if functional interactions between AT1 and AT2 receptors exist in a single neuron. Ang II caused two unique electrophysiological responses characteristic of receptor crosstalk. First, Ang II elicited an AT1 receptor-mediated decrease in IK followed by an AT2 receptor-mediated increase in IK. Second, Ang II elicited an AT2 receptor-mediated increase in IK followed by an AT1 receptor-mediated decrease in IK. AT1 and AT2 receptors were co-localized on the catecholaminergic neurons. These observations suggest, for the first time, the existence of a crosstalk between Ang II receptor subtypes that may be significant in the physiological activity of catecholaminergic neurons.

Angiotensin II Type 1 Receptor–Mediated Inhibition of K+ Channel Subunit Kv2.2 in Brain Stem and Hypothalamic Neurons

Angiotensin II (Ang II) has powerful modulatory actions on cardiovascular function that are mediated by specific receptors located on neurons within the hypothalamus and brain stem. Incubation of neuronal cocultures of rat hypothalamus and brain stem with Ang II elicits an Ang II type 1 (AT1) receptor-mediated inhibition of total outward K+ current that contributes to an increase in neuronal firing rate. However, the exact K+ conductance(s) that is inhibited by Ang II are not established. Pharmacological manipulation of total neuronal outward K+ current revealed a component of K+ current sensitive to quinine, tetraethylammonium, and 4-aminopyridine, with IC50 values of 21.7 micromol/L, 1.49 mmol/L, and 890 micromol/L, respectively, and insensitive to alpha-dendrotoxin (100 to 500 nmol/L), charybdotoxin (100 to 500 nmol/L), and mast cell degranulating peptide (1 micromol/L). Collectively, these data suggest the presence of Kv2.2 and Kv3.1b. Biophysical examination of the quinine-sensitive neuronal K+ current demonstrated a macroscopic conductance with similar biophysical properties to those of Kv2.2 and Kv3.1b. Ang II (100 nmol/L), in the presence of the AT2 receptor blocker PD123,319, elicited an inhibition of neuronal K+ current that was abolished by quinine (50 micromol/L). Reverse transcriptase-polymerase chain reaction analysis confirmed the presence of Kv2.2 and Kv3.1b mRNA in these neurons. However, Western blot analyses demonstrated that only Kv2.2 protein was present. Coexpression of Kv2.2 and the AT1 receptor in Xenopus oocytes demonstrated an Ang II-induced inhibition of Kv2.2 current. Therefore, these data suggest that inhibition of Kv2.2 contributes to the AT1 receptor-mediated reduction of neuronal K+ current and subsequently to the modulation of cardiovascular function.