Modulation of K+ and Ca2+ currents in cultured neurons by an angiotensin II type 1a receptor peptide

1997 ◽  
Vol 273 (3) ◽  
pp. C1040-C1048 ◽  
Author(s):  
M. Zhu ◽  
R. R. Neubig ◽  
S. M. Wade ◽  
P. Posner ◽  
C. H. Gelband ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
G Protein ◽  
At1 Receptor ◽  
Delayed Rectifier ◽  
Cultured Neurons ◽  
Ang Ii ◽  
Cytoplasmic Loop ◽  
At1 Receptors ◽  
The Third ◽  
Intracellular Changes

Angiotensin II (ANG II) inhibits delayed rectifier K+ current (IK) and stimulates total Ca2+ current (ICa) in neurons cocultured from newborn rat hypothalamus and brain stem, effects mediated via ANG II type 1 (AT1) receptors. Here, we identify potential G protein activator regions of the AT1 receptor responsible for initiating the intracellular changes that lead to alterations in these currents. Intracellular application into cultured neurons of a peptide corresponding to the third cytoplasmic loop of the AT1 receptor (AT1a/i3) mimicked the actions of ANG II on IK and ICa, whereas application of a peptide corresponding to the second cytoplasmic loop (AT1a/i2) did not alter these currents. This modulation of IK and ICa by AT1a/i3 involves intracellular messengers (G alpha q, protein kinase C, and intracellular Ca2+) that are identical to those involved in the modulation of IK and ICa following ANG II activation of AT1 receptors. These data provide functional evidence for a role of the third cytoplasmic loop of the AT1 receptor in G protein coupling and subsequent modulation of ion channel effectors.

scholarly journals Enhanced hemodynamic responses to angiotensin II in diabetes are associated with increased expression and activity of AT1 receptors in the afferent arteriole

2017 ◽  
Vol 49 (10) ◽  
pp. 531-540 ◽  
Author(s):  
Jie Zhang ◽  
Helena Y. Qu ◽  
Jiangping Song ◽  
Jin Wei ◽  
Shan Jiang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Mrna Level ◽  
At1 Receptor ◽  
Receptor Expression ◽  
Ang Ii ◽  
Diabetic Mice ◽  
At1 Receptors ◽  
Enhanced Expression ◽  
Bolus Intravenous Injection

The prevalence of hypertension is about twofold higher in diabetic than in nondiabetic subjects. Hypertension aggravates the progression of diabetic complications, especially diabetic nephropathy. However, the mechanisms for the development of hypertension in diabetes have not been elucidated. We hypothesized that enhanced constrictive responsiveness of renal afferent arterioles (Af-Art) to angiotensin II (ANG II) mediated by ANG II type 1 (AT1) receptors contributes to the development of hypertension in diabetes. In response to an acute bolus intravenous injection of ANG II, alloxan-induced diabetic mice exhibited a higher mean arterial pressure (MAP) (119.1 ± 3.8 vs. 106.2 ± 3.5 mmHg) and a lower renal blood flow (0.25 ± 0.07 vs. 0.52 ± 0.14 ml/min) compared with nondiabetic mice. In response to chronic ANG II infusion, the MAP measured with telemetry increased by 55.8 ± 6.5 mmHg in diabetic mice, but only by 32.3 ± 3.8 mmHg in nondiabetic mice. The mRNA level of AT1 receptor increased by ~10-fold in isolated Af-Art of diabetic mice compared with nondiabetic mice, whereas ANG II type 2 (AT2) receptor expression did not change. The ANG II dose-response curve of the Af-Art was significantly enhanced in diabetic mice. Moreover, the AT1 receptor antagonist, losartan, blocked the ANG II-induced vasoconstriction in both diabetic mice and nondiabetic mice. In conclusion, we found enhanced expression of the AT1 receptor and exaggerated response to ANG II of the Af-Art in diabetes, which may contribute to the increased prevalence of hypertension in diabetes.

Angiotensin II type 2 receptor-modulated changes in potassium currents in cultured neurons

1993 ◽  
Vol 265 (3) ◽  
pp. C607-C616 ◽  
Author(s):  
J. Kang ◽  
C. Sumners ◽  
P. Posner
Keyword(s):  
Angiotensin Ii ◽  
Ionic Current ◽  
Delayed Rectifier ◽  
Receptor Subtype ◽  
Cultured Neurons ◽  
Ang Ii ◽  
Maximal Conductance ◽  
K Current ◽  
At2 Receptors

We have previously shown that angiotensin II (ANG II) stimulates an increase in net outward ionic current (Ino) in neurons cocultured from neonate rat hypothalamus and brain stem, an effect mediated by ANG II type 2 (AT2) receptors. Ino consists mainly of K+ and Ca2+ currents, and in the present study we used whole cell voltage clamp procedures to define which of these currents are modulated by AT2 receptors. We determined that ANG II (50-100 nM) stimulated both transient K+ current (IA) and delayed-rectifier K+ current (IK) in cultured neurons. The effects were mediated by AT2 receptors (blocked by 1 microM PD-123177 but not by 1 microM losartan). For both IA and IK, ANG II elicited an increase in maximal conductance. By contrast, ANG II altered neither Ca(2+)-activated K+ current nor Ca2+ current. Our data demonstrate discrete AT2 receptor-mediated effects of ANG II on IA and IK in cultured neonate neurons. Importantly, these data provide an electrophysiological basis for behavioral or physiological effects (as yet undefined) mediated by this ANG II receptor subtype in the brain.

scholarly journals Distinctions between non-peptide angiotensin II AT1-receptor antagonists

2001 ◽  
Vol 2 (1_suppl) ◽  
pp. S24-S31 ◽  
Author(s):  
Georges Vauquelin ◽  
Frederik LP Fierens ◽  
Ilse Verheijen ◽  
Patrick ML Vanderheyden
Keyword(s):  
Angiotensin Ii ◽  
Inositol Phosphate ◽  
At1 Receptor ◽  
Maximal Response ◽  
Ang Ii ◽  
Receptor Antagonists ◽  
Experimental Conditions ◽  
At1 Receptors ◽  
At1 Receptor Antagonists ◽  
Slow Dissociation

A far-reaching understanding of the molecular action mechanism of AT1-receptor antagonists (AIIAs) was obtained by using CHO cells expressing transfected human AT 1-receptors. In this model, direct [3H]-antagonist binding and inhibition of agonist-induced responses (inositol phosphate accumulation) can be measured under identical experimental conditions. Whereas preincubation with a surmountable AIIA (losartan) causes parallel shifts of the angiotensin II (Ang II) concentration-response curve, insurmountable antagonists also cause partial (i.e., 30% for irbesartan, 50% for valsartan, 70% for EXP3174,) to almost complete (95% for candesartan) reductions of the maximal response. The main conclusions are that all investigated antagonists are competitive with respect to Ang II. They bind to a common or overlapping site on the receptor in a mutually exclusive way. Insurmountable inhibition is related to the slow dissociation rate of the antagonist-receptor complex (t 1/2 of 7 minutes for irbesartan, 17 minutes for valsartan, 30 minutes for EXP3174 and 120 minutes for candesartan). Antagonist-bound AT1-receptors can adopt a fast and a slow reversible state. This is responsible for the partial nature of the insurmountable inhibition. The long-lasting effect of candesartan, the active metabolite of candesartan cilexetil, in vascular smooth muscle contraction studies, as well as in in vivo experiments on rat and in clinical studies, is compatible with its slow dissociation from, and continuous recycling between AT1-receptors. This recycling, or `rebinding' takes place because of the very high affinity of candesartan for the AT1-receptor.

Angiotensin II-induced thirst, but not sodium appetite, via AT1 receptors in organum cavum prelamina terminalis

1995 ◽  
Vol 268 (6) ◽  
pp. R1401-R1405 ◽  
Author(s):  
M. el Ghissassi ◽  
S. N. Thornton ◽  
S. Nicolaidis
Keyword(s):  
Angiotensin Ii ◽  
Salt Intake ◽  
High Sensitivity ◽  
Ang Ii ◽  
Nacl Solution ◽  
At1 Receptors ◽  
Sodium Appetite ◽  
Specific Antagonist

The angiotensin receptor specificity, with respect to fluid intake, of the organum cavum prelamina terminalis (OCPLT), a recently discovered discrete forebrain structure with high sensitivity to angiotensin II (ANG II), was investigated. ANG II (10 ng) microinjected into the OCPLT significantly increased water consumption but did not induce intake of a hypertonic (3%) NaCl solution. Losartan, an ANG II type 1 (AT1) receptor-specific antagonist, produced dose-related (1-100 ng) inhibition of ANG II-induced drinking. The ANG II type 2 receptor-specific antagonist CGP-42112A was ineffective. Intake of the 3% NaCl solution in response to microinjection of either of the antagonists into the OCPLT was never observed. These findings suggest that water intake produced by microinjection of ANG II into the OCPLT is mediated by AT1 receptors uniquely and that, in contrast to other regions of the brain, these receptors do not induce salt intake when stimulated by ANG II.

scholarly journals The angiotensin type 2 receptor of angiotensin II and neuronal differentiation: from observations to mechanisms

2003 ◽  
Vol 31 (3) ◽  
pp. 359-372 ◽  
Author(s):  
L Gendron ◽  
MD Payet ◽  
N Gallo-Payet
Keyword(s):  
Angiotensin Ii ◽  
Neuronal Differentiation ◽  
G Protein ◽  
Cellular Migration ◽  
Ang Ii ◽  
Altered Expression ◽  
Signaling Mechanisms ◽  
Angiotensin Type 2 Receptor ◽  
G Protein Coupled

The angiotensin II (Ang II) type 2 receptor (AT(2)) is a member of the seven-transmembrane domain, G-protein coupled receptor family. This receptor is ubiquitously distributed in the fetus but, in most tIssues, its expression dramatically falls in the first few hours after birth. Based on this observation, the hypothesis that this receptor could be involved in fetal development was raised and, over the past ten Years, many studies have tried to identify a role for the AT(2) receptor using many different tIssues and cell lines. To date, one of the major roles associated with the Ang II AT(2) receptor concerns its ability to induce neuronal differentiation. Indeed, in cells of neuronal origin, activation of the AT(2) receptor was shown to induce neurite outgrowth and elongation, modulate neuronal excitability, promote cellular migration and, in particular conditions, induce neuronal cell death. Regarding its signaling mechanisms, the AT(2) receptor still represents one of the most controversial G-protein coupled receptors since it does not stimulate the production of any of the classical second messengers. This review summarizes knowledge of the functions and the signaling mechanisms involved in the actions of the AT(2) receptor in neurons and cells of neuronal origin. Based on its altered expression in neurological disorders, a role for the AT(2) receptor in control of neuronal plasticity is proposed.

Interactions of cAMP-mediated vasodilators with angiotensin II in rat kidney during hypertension

1993 ◽  
Vol 265 (6) ◽  
pp. F845-F852 ◽  
Author(s):  
C. Chatziantoniou ◽  
X. Ruan ◽  
W. J. Arendshorst
Keyword(s):  
Angiotensin Ii ◽  
G Protein ◽  
Rat Kidney ◽  
Control Period ◽  
Ang Ii ◽  
Dibutyryl Camp ◽  
Renal Vasculature ◽  
Spontaneously Hypertensive ◽  
Electromagnetic Flowmetry ◽  
Wistar Kyoto

In previous studies [C. Chatziantoniou and W.J. Arendshorst. Am. J. Physiol. 263 (Renal Fluid Electrolyte Physiol. 32): F573-F580, 1992], we reported that vasodilator prostaglandins (PGs) are defective in buffering the angiotensin II (ANG II)-induced vasoconstriction in the renal vasculature of spontaneously hypertensive rats (SHR). The purpose of the present study was to determine whether this defect in SHR kidneys is specific to PGs or generalized to the action of vasodilators and to gain insight into which intracellular signal(s) mediates this abnormality. Renal blood flow (RBF; electromagnetic flowmetry) was measured in 7 wk-old anesthetized, euvolemic SHR and normotensive Wistar-Kyoto (WKY) rats pretreated with indomethacin to avoid interactions with endogenous PGs. ANG II (2 ng) was injected into the renal artery before and during continuous intrarenal infusion of fenoldopam [DA1 receptor agonist and G protein-dependent stimulator of adenosine 3',5'-cyclic monophosphate (cAMP)], forskolin (G protein-independent stimulator of cAMP), dibutyryl-cAMP (soluble cAMP), and acetylcholine (cGMP stimulator). Each vasodilator was infused at a low dose that did not affect baseline arterial pressure or RBF. In the control period, ANG II reduced RBF by 50% in both strains. Infusion of fenoldopam significantly blunted the ANG II-induced vasoconstriction in WKY, but not in SHR. In contrast, forskolin, dibutyryl-cAMP, and acetylcholine effectively buffered the vasoconstriction due to ANG II in both SHR and WKY. These results suggest that renal vasodilators acting through receptor binding to stimulate the cAMP signaling pathway are ineffective in counteracting the ANG II-induced vasoconstriction in SHR kidneys. (ABSTRACT TRUNCATED AT 250 WORDS)

Chronotropic Effect of Angiotensin II via Type 2 Receptors in Rat Brain Neurons

2001 ◽  
Vol 85 (5) ◽  
pp. 2177-2183 ◽  
Author(s):  
Mingyan Zhu ◽  
Colin Sumners ◽  
Craig H. Gelband ◽  
Philip Posner
Keyword(s):  
Angiotensin Ii ◽  
Firing Rate ◽  
Brain Stem ◽  
Neuronal Firing ◽  
Delayed Rectifier ◽  
Neuronal Cultures ◽  
Ang Ii ◽  
Chronotropic Effect ◽  
Neuronal Firing Rate

Previously, we determined that angiotensin II (Ang II) elicits an Ang II type 2 (AT2) receptor–mediated increase of neuronal delayed rectifier K+( I KV) current in neuronal cultures from newborn rat hypothalamus and brain stem. This requires generation of lipoxygenase (LO) metabolites of arachidonic acid (AA) and activation of serine/threonine phosphatase type 2A (PP-2A). Enhancement of I KV results in a decrease in net inward current during the action potential (AP) upstroke as well as shortening of the refractory period, which may lead to alterations in neuronal firing rate. Thus, in the present study, we used whole-cell current clamp recording methods to investigate the AT2 receptor–mediated effects of Ang II on the firing rate of cultured neurons from the hypothalamus and brain stem. At room temperature, these neurons exhibited spontaneous APs with an amplitude of 77.72 ± 2.7 mV ( n = 20) and they fired at a frequency of 0.8 ± 0.1 Hz ( n = 11). Most cells had a prolonged early after-depolarization that followed an initial fully developed AP. Superfusion of Ang II (100 nM) plus losartan (LOS, 1 μM) to block Ang II type 1 receptors elicited a significant chronotropic effect that was reversed by the AT2 receptor inhibitor PD 123,319 (1 μM). LOS alone had no effect on any of the parameters measured. The chronotropic effect of Ang II was reversed by the general LO inhibitor 5,8,11,14-eicosatetraynoic acid (10 μM) or by the selective PP-2A inhibitor okadaic acid (1 nM) and was mimicked by the 12-LO metabolite of AA 12-(S)-hydroxy-(5Z, 8Z, 10E, 14Z)-eicosatetraynoic acid. These data indicate that Ang II elicits an AT2 receptor–mediated increase in neuronal firing rate, an effect that involves generation of LO metabolites of AA and activation of PP-2A.

Angiotensin II type 1 receptor modulation of neuronal K+ and Ca2+ currents: intracellular mechanisms

1996 ◽  
Vol 271 (1) ◽  
pp. C154-C163 ◽  
Author(s):  
C. Sumners ◽  
M. Zhu ◽  
C. H. Gelband ◽  
P. Posner
Keyword(s):  
Angiotensin Ii ◽  
At1 Receptor ◽  
Ang Ii ◽  
Receptor Modulation ◽  
Kinase C ◽  
Intracellular Messengers ◽  
Voltage Dependent ◽  
K Current ◽  
Stimulation Of

Angiotensin II (ANG II) elicits an ANG II type 1 (AT1) receptor-mediated decrease in voltage-dependent K+ current (Ik) and an incrase in voltage-dependent Ca2+ current (ICa) in neurons cocultured from newborn rat hypothalamus and brain stem. Modulation of these currents by ANG II involves intracellular messengers that result from an AT1 receptor-mediated stimulation of phosphoinositide hydrolysis. For example, the effects of ANG II on IK and ICa were abolished by phospholipase C antagonists. The reduction in IK produced by ANG II was attenuated by either protein kinase C (PKC) antagonists or by chelation of intracellular Ca2+. By contrast, PKC antagonism abolished the stimulatory effect of ANG II on ICa. Superfusion of the PKC activator phorbol 12-myristate 13-acetate produced effects on IK and ICa similar to those observed after ANG II. Furthermore, intracellular application of inositol 1,4,5-trisphosphate (IP3) elicited a significant reduction in IK. This suggests that the AT1 receptor-mediated changes in neuronal K+ and Ca2+ currents involve PKC (both IK and ICa) and IP3 and/or intracellular Ca2+ (IK).

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