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Introduction
α1-Adrenergic receptors (AR) are members of the G
protein-coupled receptor (GPCR) superfamily that mediate
physiological responses to norepinephrine (NE) and epinephrine
(EPI). Pharmacological analysis and molecular cloning have
shown that this receptor family has three subtypes
(α1A, α1B,
α1D), which have different pharmacological properties and
amino acid sequences[1]. Four C-terminal splice variants of
the α1A-AR have been
found[2,3]. Stimulation of all three subtypes results in activation of the
Gq/11 signaling pathway, involving activation of phospholipase C, generation of the
second messengers inositol (1,4,5) triphosphate and
diacylglycerol, and mobilization of intracellular calcium.
Because of their clinical importance, research on
α1-AR has been very active for many years. Several recent reviews
have summarized this research from different
perspectives[4-9]. In this review, we mainly focus on recent developments in
subtype-selective drugs, genetically engineered mouse
models, interacting proteins, receptor dimerization, and
factors controlling receptor cell surface expression.
α1-AR subtype selective drugs
Although all three α1-AR subtypes activate the same
Gq/11 protein signaling pathway, their different tissue distributions
suggest that they play distinct functional roles. For example,
the α1A-AR subtype has been considered to be the dominant
receptor subtype controlling benign prostatic hypertrophy,
and is an important therapeutic target for treatment of this
disease[10]. Therefore, identifying the specific functions of
individual α1-AR subtypes is of considerable therapeutic
interest. Unfortunately, this has proved difficult because of
difficulties in identifying highly subtype-selective drugs.
Despite extensive efforts to address this difficulty, only a
few subtype-selective compounds have been
characterized[11,12]. WB
4101[13],
(+)-niguldipine[14], and
5-methylurapidil[15] have been used extensively as
α1A-AR selective antagonists, and
BMY7378[16] is widely used to characterize
α1D-AR. However, there has been little progress in identifying
α1B-AR selective antagonists. Chlorethyclonidine was originally
characterized as an α1B-AR selective site-directed alkylating
agent[17]; however, it has limited selectivity in alkylating the cloned
subtypes, and is no longer widely used. Recently, a
conopeptide isolated from a sea snail, known as ρ-TIA, was
identified as a non-competitive α1B-AR
antagonist[18,19] that may serve as an allosteric modulator,
but acts as a competitive inhibitor at the other two
subtypes[20,21]. This suggests that ρ-TIA may interact with a novel antagonist binding site
specific to the α1B-AR and serve as a template for
development of highly selective α1B-AR drugs.
Genetically engineered mouse models
Since attempts to elucidate the function of individual
receptor subtypes has been limited by a lack of agonists,
antagonists, and antibodies with adequate subtype selectivity,
recent studies using genetically engineered mice have shed
some light on the contributions of each subtype to
physiological responses to NE and EPI. In general,
α1-AR knockout mice do not show overt physical abnormalities (Table 1).
Studies in knockout mice lacking a single
α1-AR subtype have shown that all three subtypes seem to be involved in
the regulation of blood pressure. Consistent with previous
pharmacological characterization in vitro, studies in
α1D-AR knockout mice have shown that the
α1D-AR subtype plays a dominant role in aortic
contraction[22]. Not only do genetically engineered mouse models help clear up some of the
confusing cardiovascular effects mediated by individual
subtypes, they also provide clues as to the functional roles
of each subtype in the central nervous system, where these
receptors are expressed in high concentrations, but their
functions have been difficult to determine. The involvement of
α1B-AR in the regulation of locomotion has been suggested
by pharmacological manipulation[23]. Interestingly,
knockout mice lacking α1B-AR also showed decreased locomotor
hyperactivity in response to psychostimulants and opiates,
suggesting that targeting the α1B-AR might be a useful
therapeutic strategy in the treatment of drug
abuse[24]. In addition to the altered phenotypes being examined in the knockout or
transgenic models, the underlying molecular mechanisms
have been investigated using olignucleotide microarrays.
Alteration in the expression of NMDA receptors,
GABAA receptors, and apoptotic and calcium regulatory genes shown
in transgenic murine brains may provide a potential
molecular basis for neurodegeneration induced by overexpressed
constitutively active
α1B-AR[25]. Despite the new insights
provided by the genetically engineered studies, some
discrepancies have been noticed from different studies, such
as the contribution of α1B-AR in the aortic contractile
response[26,27]. In addition, some of the altered phenotypes
observed in the α1B-AR knockout model may result from
compensatory effects of other receptor
subtypes[28]. Further investigation using classic pharmacological approaches with
highly subtype-selective drugs would be useful to facilitate
future interpretations of those data.
Receptor interacting proteins
Recent studies have revealed that GPCR can interact with
various cellular proteins in addition to the cognate G proteins,
thereby expanding the receptor signaling network and
establishing the distinct functional roles of closely-related
receptor subtypes within the same
family[29,30]. Those interacting proteins include cytoplasmic and membrane proteins that
may play regulatory roles in receptor pharmacology,
trafficking and signaling[31]. Although all three
α1-AR subtypes couple to
Gq/11 signaling pathways, previous studies have
shown that the three subtypes can activate distinct
downstream signaling components in the
Gq/11 signaling pathway or couple to different signaling
pathways[1]. Because of their relatively long C-termini, which have the least sequence
homology among the three subtypes, most attention has been
focused on finding binding partners interacting with this
region. In addition, the sequence diversity in the third
intracellular loop (I3 loop) is also attractive due to its importance
in coupling to Gq/11. In a similar manner, it has been shown
that the three b-AR subtypes differentially associate with a
variety of proteins other than G
proteins[32]. However, only a handful of interacting proteins have been identified for
α1-AR subtypes (Table 2). A few of these interactions have
been shown to have functional consequences, but most of
them require further evaluation. For example, gC1qR and the
mu2 subunit of the AP2 clathrin adaptor complex are involved
in α1B-AR trafficking or internalization. Although
transglutaminase II (Gh) is the first
non-Gq/11 binding partner found to specifically associate with the
α1B- and α1D-AR[33,
34], the α1-AR signaling pathways seem to remain intact in Gh
knockout mice[35]. Nevertheless, the search for novel
binding partners should be considered as an alternative approach
to study the molecular differences among the three
α1-AR subtypes.
Receptor dimerization
Unlike the conventional view that GPCR are monomers, a
growing body of evidence indicates that GPCR are able to
form dimers or oligomers that are required for their
pharmacology, function and/or cell surface expression. This
concept has gained great appreciation for the class III GPCR
subfamily, including the GABAB
receptors[36,37] and taste
receptors[38]. However, the significance of class I GPCR
dimerization has been under debate, due to difficulties in
identifying unique functional responses or pharmacological
properties. Our group has shown that the three
α1-AR subtypes can form homodimers and subtype-specific
heterodimers with other AR[39,40], which has been confirmed
by data from other groups[41,42]. Because truncation of either
the amino or the carboxyl terminus of the receptor does not
affect receptor dimerization[40], the transmembrane domains
or associated loops have been proposed to be involved in
this interaction. Because the pharmacological analyses of
the three cloned α1-AR subtypes in heterologous
expression systems have not yet recapitulated all the receptor
subtypes previously defined by pharmacological criteria in
tissues, such as the
α1L-AR[43], the newly found receptor
dimers have been hypothesized to perform atypical
α1-AR pharmacology, which has been seen in the opioid receptor
family[44]. Although the homo- or heterodimers formed by
α1A-AR C-terminal splice variants have failed to show any
novel pharmacology when studied with existing selective
drugs[45], it is still hard to conclude that the dimerization does
not have effects on receptor pharmacology, because the
available drugs are limited and the particular receptor dimers
may yet be identified. On the other hand, the
α1-AR subtype-specific dimerization has been found to be important
for receptor trafficking and signaling (summarized in the next
section).
α1D-AR cell surface expression
Theoretically, all three α1-AR subtypes should be present
at the cell surface to be recognized by their highly
hydrophilic natural ligands that are unlikely to cross cell
membranes. However, when expressed in recombinant
systems, the α1D-AR subtype has been noted to show
almost exclusively intracellular
expression[46,47], which makes them difficult to characterize. We recently reported that cell
surface expression of the α1D-AR could be specifically
rescued by coexpression with the α1B-AR but not the
α1A-AR[48]. The coexpressed receptors seem to form a new receptor entity,
and then modulate signaling and internalization of each
receptor subtype in the complex. Recently, the
b2-AR was also reported to be able to translocate
α1D-AR[49]. Besides receptor dimerization, removal of the long amino-terminus of
the α1D-AR has also been shown to facilitate translocation
of intracellular receptors to the cell
surface[50]. Subsequent studies using receptor N-terminal chimeras showed that this
N-terminal domain might convey a retention signal to
prevent receptor cell surface
expression[51]. Moreover, the density of
α1D-AR cell surface expression was shown to increase
upon sequential truncation[52].
Future directions
In the past few years, our knowledge of the functional
roles of the α1-AR family has been dramatically expanded
using many different approaches. These findings generate
several interesting directions that may be worth pursuing.
1 Further development of highly subtype-selective
drugs, especially non-competitive antagonists: most of the
specific α1-AR drugs available are competitive antagonists
with moderate subtype-selectivity, which also target other
cell surface proteins. Since the three
α1-AR subtypes have relatively high homologies among the transmembrane
domains that are believed to form the ligand binding pocket,
designing new subtype-selective drugs that compete for this
site has not been easy. However, development of
noncompetitive drugs may be a good strategy because those drugs
normally recognize a different site with less homology. This
strategy has been successfully applied in designing highly
subtype-selective drugs for other
GPCR[53].
2 Investigate the physiological relevance of receptor
oligomers: the success of this direction requires the advance
of two other research fields, characterization of
subtype-specific antibodies and development of new
α1-AR drugs. Although receptor dimerization and protein-protein
interactions have been identified in
recombinant systems, and their importance in advancing our knowledge of the
α1-AR family has been recognized, their physiological relevance
in vivo cannot be confirmed and exploited without subtype-specific
antibodies. On the other hand, new subtype-selective drugs
may recognize the discrete pharmacology of receptor dimers,
therefore expanding the existing cloned
α1-AR family and providing new therapeutic targets.
3 Characterize subtype-specific interacting proteins: the
growing list of GPCR interacting proteins has elucidated the
molecular mechanisms of the differences among subtypes,
which could lead to the development of drugs specifically
targeting to such interactions. Because previous evidence
suggests that the three α1-AR subtypes might couple to
different signaling pathways, it is likely that more interacting
proteins would be identified through the approaches that
have been successfully used, such as yeast two-hybrid
screenings and pull-down assays with fusion proteins.
4 Study the functional role of
α1-AR in the central nervous
system[5]. In fact, almost all typical and atypical
antipsychotics are α1-AR antagonists, although they show
little, if any, subtype selectivity[54]. In addition, tricyclic
antidepressants are also α1-AR antagonists, and it is possible
that this property may contribute to their therapeutic efficacy.
We believe that studies focusing on those directions would
further improve our understanding of the functional roles of
each α1-AR subtype.
References
1 Zhong H, Minneman KP. Alpha1-adrenoceptor subtypes. Eur J
Pharmacol 1999; 375: 261-76.
2 Hirasawa A, Shibata K, Horie K, Takei Y, Obika K, Tanaka
T, et
al. Cloning, functional expression and tissue distribution of
human alpha 1c-adrenoceptor splice variants. FEBS Lett 1995;
363: 256-60.
3 Chang DJ, Chang TK, Yamanishi SS, Salazar FH, Kosaka AH,
Khare R, et al. Molecular cloning, genomic characterization and
expression of novel human alpha1A-adrenoceptor isoforms.
FEBS Lett 1998; 422: 279-83.
4 Piascik MT, Perez DM. Alpha1-adrenergic receptors: new
insights and directions. J Pharmacol Exp Ther 2001; 298: 403-10.
5 Pupo AS, Minneman KP. Adrenergic pharmacology: focus on
the central nervous system. CNS Spectrums 2001; 6: 656-62.
6 Tanoue A, Koshimizu TA, Tsujimoto G. Transgenic studies of
alpha(1)-adrenergic receptor subtype function. Life Sci 2002;
71: 2207-15.
7 Hague C, Chen Z, Uberti M, Minneman KP.
alpha(1)-Adrenergic receptor subtypes: non-identical triplets with different
dancing partners? Life Sci 2003; 74: 411-8.
8 Koshimizu TA, Tanoue A, Hirasawa A, Yamauchi J, Tsujimoto G.
Recent advances in alpha1-adrenoceptor pharmacology.
Pharmacol Ther 2003; 98: 235-44.
9 Hawrylyshyn KA, Michelotti GA, Coge F, Guenin SP, Schwinn
DA. Update on human alpha1-adrenoceptor subtype signaling
and genomic organization. Trends Pharmacol Sci 2004; 25:
449-55.
10 Nagarathnam D, Wetzel JM, Miao SW, Marzabadi MR, Chiu G,
Wong WC, et al. Design and synthesis of novel alpha1a
adrenoceptor-selective dihydropyridine antagonists for the
treatment of benign prostatic hyperplasia. J Med Chem 1998; 41:
5320-33.
11 Hancock AA. alpha1-adrenoceptor subtypes: a synopsis of their
pharmacology and molecular biology. Drug Dev Res 1996; 39:
54-107.
12 Romeo G, Materia L, Salerno L, Russo F, Minneman KP. Novel
antagonists for alpha1-adrenoceptor subtypes. Expert Opin Ther
Patents 2004; 14: 619-37.
13 Morrow AL, Creese I. Characterization of alpha 1-adrenergic
receptor subtypes in rat brain: a reevaluation of
[3H]WB4104 and [3H]prazosin binding. Mol Pharmacol 1986; 29: 321-30.
14 Boer R, Grassegger A, Schudt C, Glossmann H. (+)-Niguldipine
binds with very high affinity to Ca2+ channels and to a subtype of
alpha 1-adrenoceptors. Eur J Pharmacol 1989; 172: 131-45.
15 Gross G, Hanft G, Rugevics C. 5-Methyl-urapidil discriminates
between subtypes of the alpha 1-adrenoceptor. Eur J Pharmacol
1988; 151: 333-5.
16 Goetz AS, King HK, Ward SD, True TA, Rimele TJ, Saussy DL.
BMY 7378 is a selective antagonist of the D subtype of alpha
1-adrenoceptors. Eur J Pharmacol 1995; 272: R5-6.
17 Han C, Abel PW, Minneman KP. Heterogeneity of alpha
1-adrenergic receptors revealed by chlorethylclonidine. Mol
Pharmacol 1987; 32: 505-10.
18 Sharpe IA, Gehrmann J, Loughnan ML, Thomas L, Adams DA,
Atkins A, et al. Two new classes of conopeptides inhibit the
alpha1-adrenoceptor and noradrenaline transporter. Nat Neurosci
2001; 4: 902-7.
19 Sharpe IA, Thomas L, Loughnan M, Motin L, Palant E, Croker
DE, et al. Allosteric alpha 1-adrenoreceptor antagonism by the
conopeptide rho-TIA. J Biol Chem 2003; 278: 34451-7.
20 Chen Z, Rogge G, Hague C, Alewood D, Colless B, Lewis
RJ, et al.
Subtype-selective noncompetitive or competitive inhibition of
human alpha1-adrenergic receptors by rho-TIA. J Biol Chem
2004; 279: 35326-33.
21 Lima V, Mueller A, Kamikihara SY, Raymundi V, Alewood D,
Lewis RJ, et al. Differential antagonism by conotoxin rho-TIA
of contractions mediated by distinct alpha1-adrenoceptor
subtypes in rat vas deferens, spleen and aorta. Eur J Pharmacol
2005; 508: 183-92.
22 Tanoue A, Nasa Y, Koshimizu T, Shinoura H, Oshikawa S, Kawai
T, et al. The alpha(1D)-adrenergic receptor directly regulates
arterial blood pressure via vasoconstriction. J Clin Invest 2002;
109: 765-75.
23 Stone EA, Lin Y, Itteera A, Quartermain D. Pharmacological
evidence for the role of central alpha 1B-adrenoceptors in the
motor activity and spontaneous movement of mice.
Neuropharmacology 2001; 40: 254-61.
24 Drouin C, Darracq L, Trovero F, Blanc G, Glowinski J, Cotecchia
S, et al. Alpha1b-adrenergic receptors control locomotor and
rewarding effects of psychostimulants and opiates. J Neurosci
2002; 22: 2873-84.
25 Yun J, Gaivin RJ, McCune DF, Boongird A, Papay RS, Ying
Z, et al. Gene expression profile of neurodegeneration induced by
alpha1B-adrenergic receptor overactivity:
NMDA/GABAA dysregulation and apoptosis. Brain 2003; 126: 2667-81.
26 Cavalli A, Lattion AL, Hummler E, Nenniger M, Pedrazzini T,
Aubert JF, et al. Decreased blood pressure response in mice
deficient of the alpha1b-adrenergic receptor. Proc Natl Acad Sci
USA 1997; 94: 11589-94.
27 Cavalli A, Lattion AL, Hummler E, Nenniger M, Pedrazzini T,
Aubert JF, et al. A knockout approach indicates a minor
vasoconstrictor role for vascular alpha1B-adrenoceptors in mouse.
Physiol Genomics 2002; 9: 85-91.
28 Deighan C, Woollhead AM, Colston JF, McGrath JC.
Hepatocytes from alpha1B-adrenoceptor knockout mice reveal
compensatory adrenoceptor subtype substitution. Br J Pharmacol
2004; 142: 1031-7.
29 Hall RA, Premont RT, Lefkowitz RJ. Heptahelical receptor
signaling: beyond the G protein paradigm. J Cell Biol 1999;
145:927-32.
30 Hall RA, Lefkowitz RJ. Regulation of G protein-coupled
receptor signaling by scaffold proteins. Circ Res 2002; 91: 672-80.
31 Bockaert J, Fagni L, Dumuis A, Marin P. GPCR interacting
proteins (GIP). Pharmacol Ther 2004; 103: 203-21.
32 Hall RA. Beta-adrenergic receptors and their interacting proteins.
Semin Cell Dev Biol 2004; 15: 281-8.
33 Nakaoka H, Perez DM, Baek KJ, Das T, Husain A, Misono
K, et al. Gh: a GTP-binding protein with transglutaminase activity
and receptor signaling function. Science 1994; 264: 1593-6.
34 Chen S, Lin F, Iismaa S, Lee KN, Birckbichler PJ, Graham RM.
Alpha1-adrenergic receptor signaling via Gh is subtype specific
and independent of its transglutaminase activity. J Biol Chem
1996; 271: 32385-91.
35 Nanda N, Iismaa SE, Owens WA, Husain A, Mackay F, Graham
RM. Targeted inactivation of Gh/tissue transglutaminase II. J
Biol Chem 2001; 276: 20673-8.
36 White JH, Wise A, Main MJ, Green A, Fraser NJ, Disney
GH, et al. Heterodimerization is required for the formation of a
functional GABA(B) receptor. Nature 1998; 396: 679-82.
37 Kuner R, Kohr G, Grunewald S, Eisenhardt G, Bach A, Kornau
HC. Role of heteromer formation in
GABAB receptor function. Science 1999; 283: 74-7.
38 Nelson G, Hoon MA, Chandrashekar J, Zhang Y, Ryba NJ, Zuker
CS. Mammalian sweet taste receptors. Cell 2001; 106: 381-90.
39 Vicentic A, Robeva A, Rogge G, Uberti M, Minneman KP.
Biochemistry and pharmacology of epitope-tagged
alpha(1)-adrenergic receptor subtypes. J Pharmacol Exp Ther 2002; 302:
58-65.
40 Uberti MA, Hall RA, Minneman KP. Subtype-specific
dimerization of alpha 1-adrenoceptors: effects on receptor expression
and pharmacological properties. Mol Pharmacol 2003; 64:
1379-90.
41 Stanasila L, Perez JB, Vogel H, Cotecchia S. Oligomerization of
the alpha 1a- and alpha 1b-adrenergic receptor subtypes.
Potential implications in receptor internalization. J Biol Chem 2003;
278: 40239-51.
42 Carrillo JJ, Pediani J, Milligan G. Dimers of class A G
protein-coupled receptors function via agonist-mediated
trans-activation of associated G proteins. J Biol Chem 2003; 278:
42578-87.
43 Ohmura T, Sakamoto S, Hayashi H, Kigoshi S, Muramatsu I.
Identification of alpha 1-adrenoceptor subtypes in the dog
prostate. Urol Res 1993; 21: 211-5.
44 Jordan BA, Devi LA. G-protein-coupled receptor
heterodimer-ization modulates receptor function. Nature 1999; 399:
697-700.
45 Ramsay D, Carr IC, Pediani J, Lopez-Gimenez JF, Thurlow R,
Fidock M, et al. High-affinity interactions between human
alpha1A-adrenoceptor C-terminal splice variants produce homo-
and heterodimers but do not generate the alpha1L-adrenoceptor.
Mol Pharmacol 2004; 66: 228-39.
46 McCune DF, Edelmann SE, Olges JR, Post GR, Waldrop BA,
Waugh DJ, et al. Regulation of the cellular localization and
signaling properties of the alpha(1B)- and
alpha(1D)-adrenoceptors by agonists and inverse agonists. Mol Pharmacol
2000; 57: 659-66.
47 Chalothorn D, McCune DF, Edelmann SE, Garcia-Cazarin ML,
Tsujimoto G, Piascik MT. Differences in the cellular
localization and agonist-mediated internalization properties of the
alpha(1)-adrenoceptor subtypes. Mol Pharmacol 2002; 61:
1008-16.
48 Hague C, Uberti MA, Chen Z, Hall RA, Minneman KP. Cell
surface expression of alpha 1D-adrenergic receptors is controlled
by heterodimerization with alpha 1B-adrenergic receptors. J
Biol Chem 2004; 279: 15541-9.
49 Uberti MA, Hague C, Oller H, Minneman KP, Hall RA.
Heterodimerization with {beta}2-adrenergic receptors promotes
surface expression and functional activity of
{alpha}1D-adrenergic receptors. J Pharmacol Exp Ther 2005; 313: 16-23.
50 Pupo AS, Uberti MA, Minneman KP. N-terminal truncation of
human alpha(1D)-adrenoceptors increases expression of binding
sites but not protein. Eur J Pharmacol 2003; 462: 1-8.
51 Hague C, Chen Z, Pupo AS, Schulte N, Toews ML, Minneman
KP. The N-terminus of the human alpha-1D-adrenergic
receptor prevents cell surface expression. J Pharmacol Exp Ther
2004; 309: 388-97.
52 Petrovska R, Kapa I, Klovins J, Schioth HB, Uhlen S. Addition
of a signal peptide sequence to the alpha(1D)-adrenoceptor gene
increases the density of receptors, as determined by
[(3)H]-prazosin binding in the membranes. Br J Pharmacol 2005;
144:651-9.
53 Christopoulos A, Kenakin T. G protein-coupled receptor
allosterism and complexing. Pharmacol Rev 2002; 54: 323-74.
54 Stone EA, Lin Y, Rosengarten H, Kramer HK, Quartermain D.
Emerging evidence for a central epinephrine-innervated alpha
1-adrenergic system that regulates behavioral activation and is
impaired in depression. Neuropsychopharmacology 2003;
28:1387-99.
55 Rokosh DG, Simpson PC. Knockout of the alpha
1A/C-adrenergic receptor subtype: the alpha 1A/C is expressed in resistance
arteries and is required to maintain arterial blood pressure. Proc
Natl Acad Sci USA 2002; 99: 9474-9.
56 Knauber J, Muller WE. Decreased exploratory activity and
impaired passive avoidance behaviour in mice deficient for the
alpha(1b)-adrenoceptor. Eur Neuropsychopharmacol 2000; 10: 423-7.
57 Spreng M, Cotecchia S, Schenk F. A behavioral study of alpha-1b
adrenergic receptor knockout mice: increased reaction to
novelty and selectively reduced learning capacities. Neurobiol Learn
Mem 2001; 75: 214-29.
58 Zhang H, Cotecchia S, Thomas SA, Tanoue A, Tsujimoto G,
Faber JE. Gene deletion of dopamine beta-hydroxylase and
alpha1-adrenoceptors demonstrates involvement of
catecholamines in vascular remodeling. Am J Physiol Heart Circ Physiol
2004; 287: H2106-14.
59 Burcelin R, Uldry M, Foretz M, Perrin C, Dacosta A,
Nenniger-Tosato M, et al. Impaired glucose homeostasis in mice lacking
the alpha1b-adrenergic receptor subtype. J Biol Chem 2004;
279: 1108-15.
60 Tanoue A, Koba M, Miyawaki S, Koshimizu TA, Hosoda C,
Oshikawa S, et al. Role of the alpha1D-adrenergic receptor in
the development of salt-induced hypertension. Hypertension
2002; 40: 101-6.
61 Harasawa I, Honda K, Tanoue A, Shinoura H, Ishida Y, Okamura
H, et al. Responses to noxious stimuli in mice lacking
alpha(1d)-adrenergic receptors. Neuroreport 2003; 14: 1857-60.
62 Mishima K, Tanoue A, Tsuda M, Hasebe N, Fukue Y, Egashira
N, et al. Characteristics of behavioral abnormalities in
alpha1d-adrenoceptors deficient mice. Behav Brain Res 2004; 152:
365-73.
63 O'Connell TD, Ishizaka S, Nakamura A, Swigart PM, Rodrigo
MC, Simpson GL, et al. The alpha(1A/C)- and
alpha(1B)-adrenergic receptors are required for physiological cardiac
hypertrophy in the double-knockout mouse. J Clin Invest 2003;
111:1783-91.
64 McCloskey DT, Turnbull L, Swigart P, O'Connell TD, Simpson
PC, Baker AJ. Abnormal myocardial contraction in alpha(1A)-
and alpha(1B)-adrenoceptor double-knockout mice. J Mol Cell
Cardiol 2003; 35: 1207-16.
65 Lin F, Owens WA, Chen S, Stevens ME, Kesteven S, Arthur
JF, et al. Targeted alpha(1A)-adrenergic receptor overexpression
induces enhanced cardiac contractility but not hypertrophy. Circ
Res 2001; 89: 343-50.
66 Milano CA, Dolber PC, Rockman HA, Bond RA, Venable ME,
Allen LF, et al. Myocardial expression of a constitutively active
alpha 1B-adrenergic receptor in transgenic mice induces cardiac
hypertrophy. Proc Natl Acad Sci USA 1994; 91: 10109-13.
67 Zuscik MJ, Sands S, Ross SA, Waugh DJ, Gaivin RJ, Morilak
D, et al. Overexpression of the alpha1B-adrenergic receptor causes
apoptotic neurodegeneration: multiple system atrophy. Nat Med
2000; 6: 1388-94.
68 Zuscik MJ, Chalothorn D, Hellard D, Deighan C, McGee A, Daly
CJ, et al. Hypotension, autonomic failure, and cardiac
hypertrophy in transgenic mice overexpressing the alpha 1B-adrenergic
receptor. J Biol Chem 2001; 276: 13738-43.
69 Ross SA, Rorabaugh BR, Chalothorn D, Yun J, Gonzalez-Cabrera
PJ, McCune DF, et al. The alpha(1B)-adrenergic receptor
decreases the inotropic response in the mouse Langendorff heart
model. Cardiovasc Res 2003; 60: 598-607.
70 Hague C, Bernstein LS, Ramineni S, Chen Z, Minneman KP,
Hepler JR. Selective inhibition of alpha1A-adrenergic receptor
signaling by RGS2 association with the receptor third
intracellular loop. J Biol Chem 2005; 280: 27289-95.
71 Xu Q, Zhang T, Han QD, Zhang YY. Binding between alpha
1A-adrenergic receptor and segment of bone morphogenetic
protein-1 in human embryonic cell 293. Acta Physiol Sin 2003;
55:692-8. Chinese.
72 Pupo AS, Minneman KP. Interaction of neuronal nitric oxide
synthase with alpha1-adrenergic receptor subtypes in transfected
HEK-293 cells. BMC Pharmacol 2002; 2: 17.
73 Zhang T, Xu Q, Chen FR, Han QD, Zhang YY. Yeast two-hybrid
screening for proteins that interact with alpha1-adrenergic
receptors. Acta Pharmacol Sin 2004; 25: 1471-8.
74 Wang X, Zeng W, Soyombo AA, Tang W, Ross EM, Barnes
AP, et al. Spinophilin regulates Ca(2+) signalling by binding the
N-terminal domain of RGS2 and the third intracellular loop of
G-protein-coupled receptors. Nat Cell Biol 2005; 7: 405-11.
75 Xu Z, Hirasawa A, Shinoura H, Tsujimoto G. Interaction of the
alpha(1B)-adrenergic receptor with gC1q-R, a multifunctional
protein. J Biol Chem 1999; 274: 21149-54.
76 Diviani D, Lattion AL, Abuin L, Staub O, Cotecchia S. The AP2
complex directly interacts with the alpha-1b-adrenergic
receptor and plays a role in receptor endocytosis. J Biol Chem 2003;
278: 19331-40.
77 Pupo AS, Minneman KP. Specific interactions between gC1qR
and alpha1-adrenoceptor subtypes. J Recept Signal Transduct
Res 2003; 23: 185-95.
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