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Vol. 50, Issue 2, 265-270, June 1998
MRC Brain Metabolism Unit (A.J.H) Royal Edinburgh Hospital, Edinburgh, Scotland; US-Japan Biomedical Research Laboratories (A.A.), Tulane University Medical Center, Belle Chasse, Louisiana; Department of Clinical Biochemistry (I.G.), Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel; CNRS UPR 9023 (L.J.), CCIPE, F-34094 Montpellier, France; INSERM U 410 (M.L.), Faculté de Médecine Xavier Bichat, Paris, France; CURE:VA/UCAL DDRC (J.R.P.), West Los Angeles VA Medical Center, University of California, Los Angeles, California; Life Science Resources (S.R.R.), Abberley House, Great Shelford, Cambridge, England; Laboratoire de Chimie Biologique et de la Nutrition (P.R.) Université Libre de Bruxelles, Bruxelles, Belgium; School of Medicine (S.I.S.), State University of New York at Stony Brook, Stony Brook, New York; Department of Medicine (S.P.S.), Division of Allergy and Immunology, University of California San Francisco, San Francisco, California; Digestive Diseases Branch (S.A.W.), NIDDK, National Institutes of Health, Bethesda, Maryland; Department of Psychiatry and Mental Retardation Research Center (J.A.W.), University of California Los Angeles, Los Angeles, California
I. Introduction
II. The VPAC1 Receptor
III. The VPAC2 Receptor
IV. The PAC1 Receptor
V. Proposed Nomenclature
VI. Unresolved Issues and Conclusions
Acknowledgments
References
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I. Introduction |
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Vasoactive intestinal peptide (VIPb) and pituitary adenylate cyclase-activating polypeptide (PACAP) are members of a superfamily of structurally related peptide hormones that includes glucagon, glucagon-like peptide, secretin, and growth hormone-releasing factor (GRF). At least three receptors for PACAP exist in mammals, two of which are also high-affinity receptors for VIP. This report, prepared by the IUPHAR Subcommittee on Nomenclature for Receptors for VIP and PACAP, proposes a scheme of nomenclature for these receptors (table 1).
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VIP, first isolated from porcine intestine as a 28 amino acid peptide
capable of inducing vasodilation in the canine femoral artery (Said and
Mutt, 1970
, 1972), subsequently has been shown to have many other
actions as a neuroendocrine hormone and putative neurotransmitter. The
presence of VIP and specific VIP binding sites in defined pathways in
the brain indicates that it may play an important role in central
nervous system (CNS) function (Besson et al., 1986; Martin
et al., 1987). VIP also may promote neuronal survival
(Brenneman and Eiden, 1986) and regulate glycogen metabolism in the
cerebral cortex (Sorg and Magistretti, 1992). VIP stimulates prolactin
secretion from the pituitary (Reichlin, 1988) and catecholamine release
from the adrenal medulla (Malhotra et al., 1988); in the immune system it inhibits mitogen-activated proliferation of T cells by
inhibiting interleukin-2 production (Ottaway, 1987). Other actions of
VIP include stimulation of electrolyte secretion, smooth muscle
relaxation, and protection against oxidant injury (Gozes and Brenneman,
1989; Laburthe et al., 1993; Said, 1991, 1996). In common
with the precursors of several other neuroendocrine peptides, the VIP
precursor polypeptide (prepro-VIP) contains sequences encoding
additional biologically active peptides, including peptide histidine
isoleucine (PHI; Tatemoto and Mutt, 1981), peptide histidine methionine
(PHM, the human equivalent of PHI; Itoh et al., 1983), and
peptide histidine valine (PHV), a C-terminally extended form of PHI and
PHM (Yiangou et al., 1987). PHI, PHM, and PHV probably exert
their actions through the same receptors as VIP; there presently is
little evidence for the existence of distinct receptors selective for
these peptides.
PACAP first was identified as a 38 amino acid peptide (PACAP-38) from
ovine hypothalamus that stimulated adenylyl cyclase in rat anterior
pituitary cells in culture (Miyata et al., 1989). Subsequently, a C-terminally truncated, 27 amino acid form of the
peptide (PACAP-27) was isolated from the same source (Miyata et
al., 1990). In the CNS, PACAP, and the messenger ribonucleic acid
(mRNA) encoding its precursor are most abundant in the hypothalamus, with lower levels in many other brain regions (Ghatei et
al., 1993). PACAP is also present in several peripheral tissues,
including the gastrointestinal tract, adrenal gland, and testis
(Arimura and Shioda, 1995; Ghatei et al., 1993). Although
first isolated as a hypophysiotropic hormone, the role of PACAP in the
regulation of pituitary hormone secretion is still poorly understood
(Rawlings and Hezareh, 1996). However, in the CNS, PACAP released from
retinal afferents to the rat suprachiasmatic nucleus has been proposed to function as a daytime regulator of the biological clock (Hannibal et al., 1997), and in the periphery, PACAP is thought to
function as a noncholinergic neurotransmitter stimulating catecholamine secretion from the adrenal medulla (Przywara et al., 1996)
and to regulate exocrine and endocrine secretion from the pancreas (Yada et al., 1994).
Ligand binding studies (Shivers et al., 1991) suggested the
existence of at least two distinct receptors for PACAP, one with much
greater affinity for PACAP than for VIP (the "PACAP type I
receptor") and a second with high affinity for both PACAP and VIP
(the "PACAP type II receptor"). Based on the relative potencies of
natural and synthetic VIP analogues, it was later suggested that two
types of high affinity VIP (PACAP type II) receptors existed in rat and
human tissues. In addition to the "classical" VIP receptors from
intestinal cells (Laburthe et al., 1983), a second receptor
was identified in the human SUP-T1 lymphoblast cell line (Robberecht
et al., 1988) and in lung cancer cell lines (Luis and Said,
1990). Subsequently, three high-affinity receptors for VIP and PACAP
have been cloned.
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II. The VPAC1 Receptor |
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The first recombinant receptor for VIP and PACAP to be identified
was isolated from rat lung by Ishihara et al.
(1992c); the human
homolog of this receptor also has been cloned and expressed in cell
lines (Couvineau et al., 1994; Sreedharan et al.,
1993d).
No splice variants of the receptor have been described to date. This
receptor, originally described as the VIP receptor, subsequently was
designated the VIP1 receptor (Lutz et
al., 1993), the VIP/PACAP type II receptor (Ciccarelli et
al., 1994), or PVR2 (Rawlings et al., 1995), and in our
nomenclature is classified as the VPAC1 receptor.
There are important differences between species in the pharmacology of
VPAC1 receptors (Couvineau et al.,
1996). When expressed in cell lines, the recombinant rat
VPAC1 receptor recognized VIP
(IC50, 1 nM), PHI, and PHV
(IC50, 3 nM), PACAP-27 and PACAP-38 (IC50, 1 nM), and with lower
affinity, GRF (IC50, 80 nM) and
secretin (IC50, 300 nM). The human
receptor differed from the rat receptor in its low affinity for PHI and
PHV (IC50, 1000 nM and 3000 nM, respectively) and for secretin
(IC50, 1500 nM). Two highly selective VPAC1 receptor agonists have been described. The
VIP/GRF hybrid [Lys15,
Arg16,
Leu27]VIP(1-7)GRF(8-27)-NH2
(IC50, 1 nM) is a selective
VPAC1 receptor agonist that does not activate GRF
receptors (Gourlet et al., 1997b).
[Arg16] chicken secretin
(IC50, 2 nM: Gourlet et
al., 1997b) is an agonist of both VPAC1
receptors and secretin receptors, but can be used as a highly selective
VPAC1 receptor agonist in brain and in other tissues that do not express the secretin receptor.
[Acetyl-His1,
D-Phe2, Lys15,
Arg16]VIP
(3-7)GRF(8-27)-NH2 behaves as a selective
antagonist of rat and human VPAC1 receptors
(IC50, 1 to 10 nM; Gourlet et
al., 1997a).
Messenger RNA encoding the VPAC1 receptor is
widely distributed in the CNS, most abundantly in the cerebral cortex
and hippocampus (Ishihara et al., 1992; Usdin et
al., 1994), in peripheral tissues including liver, lung, and
intestine (Ishihara et al., 1992; Sreedharan et
al., 1995; Usdin et al., 1994) and in T lymphocytes
(Delgado et al., 1996). The distribution in rat brain of
binding sites for radioiodinated [Arg16]chicken
secretin, a selective VPAC1 receptor agonist, is
similar to that of VPAC1 receptor mRNA (Vertongen
et al., 1997).
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III. The VPAC2 Receptor |
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A second receptor that responds to VIP and PACAP with comparable
affinity ("PACAP type II" pharmacology) first was cloned from the
rat olfactory bulb by Lutz et al.
(1993e) and later
published independently by Usdin et al. (1994). cDNA sequences of the cognate mouse (Inagaki et al.,
1994f) and human
(Adamou et al., 1995; Svoboda et al.,
1994g; Wei and
Mojsov, 1996) receptors have been published. No splice variants of the
receptor have been described to date. This receptor, previously
designated the VIP2 receptor (Lutz et
al., 1993), PACAPR-3 (Inagaki et al., 1994), or PVR3
(Rawlings et al., 1995), is classified in our nomenclature
as the VPAC2 receptor. When expressed in cell lines, the recombinant rat and human VPAC2
receptors recognized VIP (IC50, 3 to 4 nM), PHI, and PHV (IC50, 10 to 30 nM), PACAP-27 (IC50, 10 nM) and PACAP-38 (IC50, 2 nM), and also recognized GRF and secretin with a very low
affinity (IC50, 5000 to 30,000 nM). Two cyclic peptides that are highly selective agonists of the VPAC2 receptor have been described: Ro
25-1553h (Gourlet
et al., 1997c), first developed as a bronchorelaxant and an
anti-inflammatory agent (O'Donnell et al., 1994a,b) and Ro
25-1392i (Xia
et al., 1997). No selective VPAC2
receptor antagonist has been described to date.
In the CNS, the highest concentrations of messenger RNA encoding the
VPAC2 receptor are found in the thalamus and
suprachiasmatic nucleus (SCN) and lower levels in the hippocampus,
brainstem, spinal cord, and dorsal root ganglia (Sheward et
al., 1995; Usdin et al., 1994). The distribution in
brain of binding sites for the selective VPAC2
receptor agonist Ro 25-1553 is similar to that of
VPAC2 receptor mRNA (Vertongen et al.,
1997). The receptor is also present in several peripheral tissues,
including pancreas, skeletal muscle, heart, kidney, adipose tissue,
testis, and stomach (Adamou et al., 1995; Krempels et
al., 1995; Usdin et al., 1994; Wei and Mojsov, 1996).
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IV. The PAC1 Receptor |
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In 1993, Pisegna and Wank
(1993j) reported the
cloning and expression of a PACAP-selective (type I) receptor from the
rat pancreatic acinar carcinoma cell line AR4-2J. Within a few weeks,
several other groups independently reported the sequence of the rat
receptor (Hashimoto et al., 1993; Hosoya et al.,
1993; Morrow et al., 1993; Spengler et al., 1993;
Svoboda et al., 1993) and complementary deoxyribonucleic
acid (cDNA) sequences of the cognate mouse (Hashimoto et
al., 1996b,k
bovine (Miyamoto et al.,
1994l), and human
(Ogi et al.,
1993m) receptors have
been published. This receptor (previously the PACAP type I receptor or
PVR1; Rawlings et al., 1995) is classified in our
nomenclature as the PAC1 receptor. When expressed
in cell lines, the recombinant rat and human PAC1
receptors recognized PACAP-27 and PACAP-38 (IC50,
1 nM) with higher potency than VIP (IC50, 1000 nM) and bound PHI, PHV,
secretin, and GRF with even lower affinities (Ciccarelli et
al., 1995; P. Robberecht, unpublished data). Maxadilan, a 61 amino
acid peptide from sand flies, with no evident sequence homology with
PACAP, activates PAC1 receptors with a high
affinity (IC50, 1 to 3 nM) and does
not have a significant affinity for VPAC1 or
VPAC2 receptors (Moro and Lerner, 1997). The
PACAP fragment, PACAP(6-38) is a potent
antagonist of PAC1 receptors
(Ki, 14 nM) and does not
interact with VPAC1 receptors. However, it has a
significant affinity for VPAC2 receptors
(Dickinson et al., 1997). Messenger RNA encoding the
PAC1 receptor is expressed predominantly in the
CNS (most abundantly in the olfactory bulb, thalamus, hypothalamus, the
dentate gyrus of the hippocampus, and granule cells of the cerebellum;
Hashimoto et al., 1993, 1996a; Spengler et al.,
1993) and in the adrenal medulla (Moller and Sundler, 1996).
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V. Proposed Nomenclature |
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The nomenclature in table 1 takes account of the following
considerations: (i) the PAC1 receptor
does not respond to physiological concentrations of VIP and hence the
PVR nomenclature proposed by Rawlings (Rawlings et al.,
1995) seems inappropriate for this receptor; (ii) the scheme
permits the naming of any second PACAP specific receptor (encoded by a
different gene) that may be identified as PAC2;
(iii) the scheme minimizes possible confusion with the PVR1/PVR2/PVR3 nomenclature; (iv) the scheme accords
priority to VIP, consistent with the fact that, when first cloned, the VPAC1 and VPAC2 receptors
were named as receptors for VIP rather than PACAP; (v) the
scheme minimizes possible confusion with vasopressin receptors, which
an alternative (V1P, V2P) scheme that we considered does not.
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VI. Unresolved Issues and Conclusions |
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There are several unresolved issues that may change our view of the receptors in this family and may lead to future changes in nomenclature. The discovery of any new receptors for VIP and PACAP, or of any novel endogenous ligands for these receptors, would lead us to re-evaluate the scheme of nomenclature proposed here.
Gozes and colleagues have described several VIP analogues with potent
activity in vitro and in vivo including (i) a hybrid peptide, combining a portion of VIP with a portion of neurotensin, that
antagonized some of the behavioral actions of VIP (Gozes et
al., 1989; Hill et al., 1991), inhibited the
growth-promoting actions of VIP on the mouse embryo (Gressens et
al., 1993, 1994) and on a variety of cell lines (Lilling et
al., 1994; Moody et al., 1993; Wollman et
al., 1993), and inhibited binding of VIP to some cell types but
not to others (Gozes et al., 1989, 1991) and (ii)
a lipophilic analogue of VIP (stearyl-Nle17-VIP;
Gozes et al., 1994) which has been reported to enhance
survival of neurons in culture with 100-fold greater potency than VIP
(Gozes et al., 1995) and to be neuroprotective in animal
models of Alzheimer's disease (Gozes et al., 1996). The
nature of the receptors through which these peptides exert their
actions, whether novel or existing, remains to be established.
There is apparent heterogeneity of PAC1 receptors
in tissues and cell lines, where two types of "PACAP type I"
pharmacology have been observed: type IA receptors, with high affinity
for both PACAP-27 and PACAP-38, and type IB receptors, with high
affinity for PACAP-38 but low affinity for PACAP-27 (Robberecht
et al., 1991; Shivers et al., 1991). The
difference between the two receptor subtypes may reflect differences in
G protein coupling and second-messenger mechanisms (Van Rampelbergh
et al., 1996) or result from alternative splicing of
PAC1 receptor mRNA (Pantaloni et al.,
1996; Spengler et al., 1993). Unlike the
VPAC1 and VPAC2 receptors,
the PAC1 receptor has numerous splice variants
for which no systematic scheme of nomenclature has yet been devised.
Splice variants either containing or lacking each of two alternative
exons ("hip" and "hop") exist within the part of the
PAC1 receptor cDNA encoding the third
intracellular loop. The "hop" exon exists in two forms ("hop1"
and "hop2") as the result of the existence of two alternative splice acceptor sites three nucleotides apart. Thus, six possible splice variants which differ in their intracellular signal transduction pathways can be generated (Journot et al., 1995; Spengler
et al., 1993). Four variants of the human
PAC1 receptor (null, SV-1, SV-2, and SV-3)
resulting from alternative splicing of sequences equivalent to hip and
hop1 also have been described (Pisegna and Wank, 1996) and shown to
differ in their ability to activate phospholipase C. In addition,
splice variation in the N-terminal extracellular domain of the mouse
PAC1 receptor, leading to a 21 amino acid deletion, has been reported to influence receptor selectivity with
respect to PACAP-27 and -38 binding and to change the relative potencies of the two agonists in phospholipase C stimulation (Pantaloni et al., 1996). The significance of a novel PACAP receptor
variant, designated PACAPR TM4 transmembrane domain IV), reported to
differ from the previously cloned short form of the
PAC1 receptor primarily by discrete sequences
located in transmembrane domains II and IV (Chatterjee et
al., 1996), remains to be established.
We hope that our proposals will gain acceptance and will facilitate the communication of new findings in this rapidly developing field.
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Acknowledgments |
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We thank Drs. T.I. Bonner and S.P. Watson for liaison with the IUPHAR Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) and Dr. D. Girdlestone for helpful advice and assistance.
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Footnotes |
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a Address for correspondence: Anthony J. Harmar, MRC Brain Metabolism Unit, University Department of Pharmacology, 1 George Square, Edinburgh EH8 9JZ, UK.E-mail: Tony.Harmar{at}ed.ac.uk.
c Genbank accession no. M86835
d Genbank accession no. L13288
e Genbank accession no. Z25885
f Genbank accession no. D28132
g Genbank accession no. L36566
h Ac-His1[Glu8, Lys12, Nle17, Ala19, Asp25, Leu26, Lys27,28, Gly29,30, Thr31]-NH2 vasoactive intestinal peptide (cyclo 21-25)
i Ac-His1[Glu8, OCH3-Tyr10, Lys12, Nle17, Ala19, Asp25, Leu26, Lys27,28] vasoactive intestinal peptide (cyclo 21-25)
j Genbank accession no. L16680
k Genbank accession no. D82935
l Genbank accession no. D17290
m Genbank accession no. D17516
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Abbreviations |
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cDNA, complementary deoxyribonucleic acid; CNS, central nervous system; GRF, growth hormone-releasing factor; mRNA, messenger ribonucleic acid; PACAP, pituitary adenylate cyclase-activating polypeptide; PHI, peptide histidine isoleucine PHM, peptide histidine methionine; PHV, peptide histidine valine; SCN, suprachiasmatic nucleus; VIP, vasoactive intestinal peptide.
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References |
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In vitro and in vivo bronchodilator studies.
J Pharmacol Exp Ther
270:
1282-1288Effect on in vitro and in vivo models of pulmonary anaphylaxis.
J Pharmacol Exp Ther
270:
1289-1294
0031-6997/98/502-0265$03.00/0
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