Vascular α-adrenoceptors: from the gene to the human

1995 ◽  
Vol 73 (5) ◽  
pp. 533-543 ◽  
Author(s):  
David B. Bylund ◽  
John W. Regan ◽  
James E. Faber ◽  
J. Paul Hieble ◽  
Christopher R. Triggle ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Blood Vessel ◽  
Adenylate Cyclase ◽  
Inositol Phosphate ◽  
Second Messenger ◽  
Molecular Techniques ◽  
Cellular Growth ◽  
Site Directed Mutagenesis ◽  
Intracellular Loop ◽  
Stimulation Of

Adrenoceptors can be subdivided into three major types, the α1-, α2-, and β-adrenoceptors. Each of these types can be further subdivided into three subtypes, based on pharmacological characteristics. Molecular cloning techniques have supported this subclassification. Recent data now suggest that α-adrenoceptor subtypes identified by pharmacological and molecular techniques correspond well, although species orthologs of several adrenoceptor subtypes have been identified. The secondary structure of the adrenoceptors has been elucidated and correlated with their interaction with second messenger molecules. α1-Adrenoceptors, β-adrenoceptors, and α2-adrenoceptors mediate their actions through stimulation of inositol phosphate release, stimulation of adenylate cyclase, and inhibition of adenylate cyclase, respectively. Site-directed mutagenesis and the preparation of chimeric receptors have located the site of receptor – second messenger interaction to the third intracellular loop for each of these adrenoceptors. While subtypes of each of these classes all interact with the same second messenger, studies with recombinant α2-adrenoceptors show subtype-related differences in receptor – second messenger interaction. Multiple α-adrenoceptor subtypes are expressed in vascular smooth muscle and are involved in various aspects of blood vessel function, including contraction, cellular growth, and proliferation. Various physiological factors can selectively influence responses to a particular subtype, and the relative roles of each subtype can vary between vascular beds and along an individual blood vessel as its caliber changes. Functional studies in blood vessels suggest the presence of additional α-adrenoceptor subtypes not yet identified via molecular techniques. Optimization of the therapeutic profile of an α-adrenoceptor antagonist may be possible via enhancement of selectivity for a particular subtype or by design of a specific profile of affinity for the individual subtypes.Key words: adrenoceptor subclassification, second messenger, G-proteins, vasoconstriction, smooth muscle proliferation.

Effects of amino and ammonio derivatives of adenosine on smooth muscle preparations and mouse neuroblastoma adenylate cyclase

1985 ◽  
Vol 63 (1) ◽  
pp. 58-61 ◽  
Author(s):  
H. P. Baer ◽  
M. Morr
Keyword(s):  
Smooth Muscle ◽  
Adenylate Cyclase ◽  
Adenosine Receptors ◽  
Smooth Muscles ◽  
Mouse Neuroblastoma ◽  
Derivatives Of ◽  
Stimulation Of

Several amino- and ammonio-substituted derivatives of adenosine were tested as effectors of adenosine receptors in different smooth muscle preparations and mouse neuroblastoma adenylate cyclase. The compounds did not affect adenosine receptors in smooth muscles. N6-[3-(trimethylammonio)propyl]adenosine was a weak stimulator of adenylate cyclase, and 3′-amino-3′-deoxyadenosine and 3′-rnonomethylamino-3′-deoxyadenosine antagonized the stimulation of adenylate cyclase by 2-chloroadenosine.

scholarly journals Thrombin-induced inositol trisphosphate production by rabbit platelets is inhibited by ethanol

1988 ◽  
Vol 251 (1) ◽  
pp. 279-284 ◽  
Author(s):  
M L Rand ◽  
J D Vickers ◽  
R L Kinlough-Rathbone ◽  
M A Packham ◽  
J F Mustard
Keyword(s):  
Inositol Phosphates ◽  
Inositol Phosphate ◽  
Inositol Trisphosphate ◽  
Thromboxane A2 ◽  
Second Messenger ◽  
Inhibitory Effect ◽  
Thromboxane B2 ◽  
Rabbit Platelets ◽  
Platelet Functions ◽  
Stimulation Of

Ethanol has an inhibitory effect on some platelet functions, but the mechanisms by which it exerts this effect are not known. Using suspensions of washed platelets, we observed that ethanol (1-9 mg/ml) did not affect the aggregation of rabbit platelets stimulated with ADP (0.5-10 microM). When platelets were prelabelled with 5-hydroxy[14C]tryptamine, aggregation and secretion of granule contents in response to thrombin (0.01-0.10 unit/ml) were not inhibited by ethanol, but these responses to thrombin at lower concentrations (less than 0.01 unit/ml) were inhibited by ethanol (2-4 mg/ml). Platelets were prelabelled with [3H]inositol so that increases in inositol phosphates upon stimulation could be assessed by measuring the amount of label in these compounds. ADP-induced increases in IP (inositol phosphate) and IP2 (inositol bisphosphate) were not affected by ethanol. IP3 (inositol trisphosphate) was not changed by ADP or ethanol. Although ethanol did not affect the increases in IP, IP2 and IP3 caused by stimulation of platelets with thrombin at concentrations greater than 0.01 unit/ml, ethanol did inhibit the increases observed at 2 and 3 min in these inositol phosphates caused by lower concentrations of thrombin (less than 0.01 unit/ml). Since ADP did not cause formation of IP3 in rabbit platelets, and since no thromboxane B2 was detected in platelets stimulated with the lower concentrations of thrombin, it is unlikely that the inhibitory effect of ethanol in IP3 formation was due to effects on further stimulation of platelets by released ADP or by thromboxane A2. Ethanol may inhibit platelet responses to thrombin by inhibiting the production of the second messenger, IP3.

A consensus sequence in the endothelin-B receptor second intracellular loop is required for NHE3 activation by endothelin-1

2005 ◽  
Vol 288 (4) ◽  
pp. F732-F739 ◽  
Author(s):  
Kamel Laghmani ◽  
Aiji Sakamoto ◽  
Masashi Yanagisawa ◽  
Patricia A. Preisig ◽  
Robert J. Alpern
Keyword(s):  
Apical Membrane ◽  
Consensus Sequence ◽  
Site Directed Mutagenesis ◽  
Intracellular Loop ◽  
Additional Mechanism ◽  
Opossum Kidney ◽  
Endothelin 1 ◽  
Endothelin B ◽  
Necessary And Sufficient ◽  
Stimulation Of

Endothelin-1 (ET-1) increases the activity of Na+/H+ exchanger 3 (NHE3), the major proximal tubule apical membrane Na+/H+ antiporter. This effect is seen in opossum kidney (OKP) cells expressing the endothelin-B (ETB) and not in cells expressing the endothelin-A (ETA) receptor. However, ET-1 causes similar patterns of protein tyrosine phosphorylation, adenylyl cyclase inhibition, and increases in cell [Ca2+] in ETA- and ETB-expressing OKP cells, implying that an additional mechanism is required for NHE3 stimulation by the ETB receptor. The present studies used ETA and ETB receptor chimeras and site-directed mutagenesis to identify the ET receptor domains that mediate ET-1 regulation of NHE3 activity. We found that binding of ET-1 to the ETA receptor inhibits NHE3 activity, an effect for which the COOH-terminal tail is necessary and sufficient. ET-1 stimulation of NHE3 activity requires the COOH-terminal tail and the second intracellular loop of the ETB receptor. Within the second intracellular loop, a consensus sequence was identified, KXXXVPKXXXV, that is required for ET-1 stimulation of NHE3 activity. This sequence suggests binding of a homodimeric protein that mediates NHE3 stimulation.

scholarly journals Effect of catecholamines on Na/H exchange in vascular smooth muscle cells.

1986 ◽  
Vol 103 (5) ◽  
pp. 2053-2060 ◽  
Author(s):  
N E Owen
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Adrenergic Receptor ◽  
Inositol Phosphate ◽  
Major Pathway ◽  
Phosphate Release ◽  
Potency Order ◽  
Stimulation Of

Catecholamines were found to activate Na/H exchange in a concentration-dependent manner in primary cultures of vascular smooth muscle cells (VSMC). The potency order was found to be epinephrine greater than norepinephrine greater than isoproterenol. The major pathway for catecholamine effects appeared to be via interaction with an alpha 1 adrenergic receptor. In addition, it was found that alpha 1 receptor-mediated Na/H exchange in VSMC was increased by angiotensin II and inhibited by 12-O-tetradecanoyl phorbol-13-acetate (TPA). Adrenergic receptors have been shown to be coupled to both adenylate cyclase and to inositol phosphate release (Leeb-Lundberg, L. M. F., S. Cotecchia, J. W. Lomasney, J. F. DeBernadis, R. J. Lefkowitz, and M. G. Caron, 1985, Proc. Natl. Acad. Sci. USA, 82:5651-5655.). It was found that catecholamines increased AMP levels in the potency order isoproterenol greater than norepinephrine greater than epinephrine and the receptor involved was a beta adrenergic receptor. Since these findings did not parallel the results obtained for catecholamine stimulation of Na/H exchange, an increase in AMP levels was probably not the mechanism by which major pathway for catecholamine-stimulated Na/H exchange in VSMC (via the alpha 1 receptor) was activated. When the effects of catecholamines were measured on inositol phosphate release, the potency order for catecholamine stimulation was epinephrine greater than norepinephrine greater than isoproterenol, and the receptor involved was an alpha 1 adrenergic receptor. In addition, angiotensin II increased and TPA inhibited catecholamine-stimulated inositol phosphate release. Since these findings paralleled the results obtained for catecholamine stimulation of Na/H exchange, inositol phosphate release may be the mechanism by which the major pathway for catecholamine-stimulated Na/H exchange in VSMC (via the alpha 1 receptor) was activated.

Effect of Na-K adenosinetriphosphatase activity on relaxation of canine tracheal smooth muscle

1988 ◽  
Vol 64 (2) ◽  
pp. 635-641 ◽  
Author(s):  
S. J. Gunst ◽  
J. Q. Stropp
Keyword(s):  
Smooth Muscle ◽  
Adenylate Cyclase ◽  
Atpase Activity ◽  
Prostaglandin E2 ◽  
Sodium Nitroprusside ◽  
Tracheal Smooth Muscle ◽  
Free Medium ◽  
Inhibitory Effects ◽  
Ca2 Channels ◽  
Stimulation Of

The effect of Na-K adenosinetriphosphatase (ATPase) on relaxation induced by isoproterenol, prostaglandin E2, sodium nitroprusside, and forskolin, a specific stimulant of adenylate cyclase, was investigated in canine tracheal smooth muscle strips. Relaxation in response to isoproterenol, prostaglandin E2, and forskolin was significantly decreased after inhibition of the Na-K ATPase by ouabain or a potassium-free medium, but relaxation to sodium nitroprusside was not affected. Relaxation to isoproterenol was greater in muscles contracted by 5-hydroxytryptamine than in those contracted by acetylcholine. The stimulation of Na-K ATPase activity with potassium also caused differences in relaxation between tissues contracted with 5-hydroxytryptamine or acetylcholine. Relaxation caused by isoproterenol by activation of the Na-K-ATPase was also decreased by the Ca2+-channel antagonists, verapamil and diltiazem. The results suggest 1) Na-K ATPase activity modulates relaxation caused by isoproterenol, prostaglandin E2, and forskolin in canine tracheal smooth muscle, 2) isoproterenol or activation of the Na-K ATPase may cause relaxation partly by reducing Ca2+ influx through potential-dependent Ca2+ channels, and 3) the differences in the inhibitory effects of isoproterenol and Na-K ATPase activity on muscles contracted by acetylcholine and 5-hydroxytryptamine could be due to differences between these contractile agents in their dependence on extracellular Ca2+ for activation.

Evidence for direct non-genomic effects of triiodothyronine on bone rudiments in rats: Stimulation of the inositol phosphate second messenger system

1991 ◽  
Vol 125 (6) ◽  
pp. 603-608 ◽  
Author(s):  
Peter Lakatos ◽  
Paula H. Stern
Keyword(s):  
Plasma Membrane ◽  
Thyroid Hormones ◽  
Time Course ◽  
Inositol Phosphates ◽  
Inositol Phosphate ◽  
Second Messenger ◽  
Cytosolic Calcium ◽  
Membrane Receptors ◽  
Free Calcium ◽  
Stimulation Of

Abstract. Thyroid hormones increase cytosolic free calcium by binding to plasma membrane receptors in several tissues. This calcium increase appears to initiate extranuclear effects in these tissues. Increases in cytosolic calcium are often a consequence of stimulation of inositol phosphate second messenger pathway. Several calcemic hormones act via this signal transduction route. Therefore we investigated the effects of the metabolically active T3 and the inactive analogues 3,5-diiodotyrosine and rT3 on the inositol phosphate pathway in fetal rat limb bone cultures prelabeled with [3H]myoinositol. Labelled inositol and inositol phosphates were separated by HPLC. There was a significant increase in the radioactivity in inositol bis- and trisphosphates after 1 min of exposure to 10−7 mol/l T3. Stimulation was also observed at 10−6 mol/l T3, but not at 10−5 mol/l. Time course studies demonstrated a rapid effect of T3 on inositol phosphates within 30 seconds that lasted through 5 min. After 20 min incubation with T3, no increase was observed in inositol mono- and bisphosphates, and a decrease was seen in inositol trisphosphate. Pretreatment with indomethacin prevented these effects of T3. 3,5-diiodothyrosine and rT3 did not affect inositol phosphate metabolism. These results suggest the existence of plasma membrane-associated receptors for T3 in bone, in addition to the nuclear receptors demonstrated previously. The role of these receptors in the effects of thyroid hormones on bone remains to be established.

scholarly journals Cholera toxin modulation of angiotensin II-stimulated inositol phosphate production in cultured vascular smooth muscle cells

1990 ◽  
Vol 265 (3) ◽  
pp. 799-807 ◽  
Author(s):  
L Socorro ◽  
R W Alexander ◽  
K K Griendling
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Cyclic Amp ◽  
Vascular Smooth Muscle ◽  
Phospholipase C ◽  
Cholera Toxin ◽  
G Protein ◽  
Vascular Smooth Muscle Cells ◽  
Inositol Phosphate ◽  
Stimulation Of

Activation of phospholipase C by angiotensin II in vascular smooth muscle has been postulated to be mediated by an unidentified GTP-binding protein (G-protein). Using a permeabilized preparation of myo-[3H]inositol-labelled cultured vascular smooth muscle cells, we examined the ability of a non-hydrolysable analogue of GTP, guanosine 5′-[gamma-thio]triphosphate (GTP[S]), to stimulate inositol phosphate formation. GTP[S] (5 min exposure) stimulated inositol polyphosphate release by up to 3.8-fold in a dose-dependent manner, with an EC50 (concn. producing half-maximal stimulation) of approx. 50 microM. Inositol bisphosphate (IP2) and inositol trisphosphate (IP3) accumulations were also stimulated by NaF (5-20 mM). Furthermore, angiotensin II-induced inositol phosphate formation could be potentiated by a submaximal concentration of GTP[S] (10 microM), and this treatment appeared to interfere with the normal termination mechanism of the initial hormonal signal. The G-protein mediating angiotensin II-stimulated phospholipase C activation was insensitive to pertussis toxin at an exposure time and concentration which were sufficient to completely ADP-ribosylate all available substrate (100 ng/ml, 16 h). In contrast, a similar incubation with cholera toxin markedly inhibited angiotensin II-stimulated IP2 and IP3 release by 67 +/- 6% and 62 +/- 6% respectively. Cholera toxin appeared to inhibit angiotensin II stimulation of phospholipase C by a dual mechanism: it caused a 45% decrease in angiotensin II receptor number, and also inhibited G-protein transduction as assessed by GTP[S]-stimulated IP2 formation. This latter inhibition may be secondary to an increase in cyclic AMP, since it could be simulated by addition of dibutyryl cyclic AMP. Thus angiotensin II-stimulated inositol phosphate formation is cholera-toxin-sensitive, and is mediated by a pertussis-toxin-insensitive G-protein, which may be involved directly in termination of early signal generation.

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