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A J Harmar

Publications and source records attributed to A J Harmar.

At least 37 records · Page 2Linked to original sources
PubMed1996

Chromosomal localization in mouse and human of the vasoactive intestinal peptide receptor type 2 gene: a possible contributor to the holoprosencephaly 3 phenotype.

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) have been shown to act on a wide range of tissue and cell types, both in the central nervous system and in the periphery. Two distinct receptors for VIP, the VIP receptor type 1 (VIPR1) and the VIP receptor type 2 (VIPR2), have recently been cloned, each of which binds PACAP and VIP with equal affinity. We report here the chromosomal mapping of the human and mouse VIPR2 genes by fluorescence in situ hybridization. The VIPR2 gene maps to the human chromosomal region 7q36.3 and to the F2 region of mouse chromosome 12. Our localization of the human gene places it in the region where the locus for the craniofacial defect holoprosencephaly type 3 (HPE3) maps. Further mapping experiments, carried out on cell lines derived from patients with HPE or HPE microforms and associated 7q deletions, have led us to redefine the distal extent of the HPE3 minimal critical region, originally characterized by Gurrieri et al. (1993, Nature Genet. 3: 247-251.) The VIPR2 gene lies within this new HPE3 minimal critical region. Our results suggest that deletion of the VIPR2 gene is not the sole factor responsible for the HPE3 phenotype. However, it is possible that monosomy at the VIPR2 locus may contribute to the phenotype observed in many cases of HPE3.

Animals↗
PubMed1996

Expression of pituitary adenylate cyclase activating polypeptide receptors in the early mouse embryo as assessed by reverse transcription polymerase chain reaction and in situ hybridisation.

We have examined the expression of mRNA for the pituitary adenylate cyclase activating polypeptide (PACAP) receptor in the mouse from day 9.5 of embryonic development onwards by reverse transcription polymerase chain reaction (RT-PCR) and by in situ hybridisation. PACAP receptor mRNAs were detected by PCR in the earliest developmental stage examined and thereafter the levels of mRNA for all receptors increased during development. Wholemount in situ hybridisation first showed the expression of the PACAP receptor in the neural tube of 9.5 day old embryos, in later embryos heaviest expression of the PACAP receptor was found in the developing rhombencephalon (day 10.5 and 11.5). These results are consistent with a role for PACAP or a related peptide in the early development of the central nervous system.

Animals↗
PubMed1996

Polymorphism in serotonin transporter gene associated with susceptibility to major depression.

UNLABELLED: BACKGROUND; The serotonin transporter of the brain provides the primary target for the action of selective antidepressant drugs. We set out to identify polymorphisms of the serotonin transporter gene and to find out whether there was a relation between any such polymorphisms and the occurrence of affective disorder. METHODS: A comparison of a polymorphic region of the human serotonin transporter gene was carried out between two groups. The study group comprised 83 patients (39 unipolar depressive disorder, 44 bipolar disorder) with major affective disorder. The control group comprised 122 anonymous blood donors, and 71 volunteers who had been screened for psychiatric disorders. FINDINGS: We detected three novel alleles of the variable-number-tandem-repeat (VNTR) region (STin2.9, STin2.10) and Stin2.12) containing nine, ten and 12 copies of the VNTR element, respectively. The frequencies of the different forms of the allele in the control group were compared with those in the affective disorder group. There was a significant difference between the control and affective disorder groups, largely explained by the excess of the STin2.9 allele in the unipolar group (chi2=10.05, p<0.004 [Bonferroni corrected]). The presence of the allele with nine copies of the repeat was significantly associated with risk of unipolar disorder (odds ratio=6.95 [95% CI 1.8-27.2]). INTERPRETATION: This association, for an obvious candidate gene, may provide a critical starting point for an understanding of the likely polygenic contributions towards susceptibility to affective disorder.

Alleles↗
PubMed1996

Structure of a variable number tandem repeat of the serotonin transporter gene and association with affective disorder.

We have recently reported an association between a polymorphism of a variable number tandem repeat (VNTR) region of the serotonin transporter gene and susceptibility to major depressive disorder. We identified three alleles containing respectively 9 (STin2.9), 10 (STin2.10) and 12 (STin2.12) copies of a repetitive element. We report here the sequences of the three alleles. The repetitive element conformed to the consensus sequence, GGCTGYGACCY(R)GRRTG, where Y = T/C, R = G/A, with loss of the 12th base pair in one of the repeating elements. We have also extended the numbers of cases and controls in the study. The frequencies of the three alleles in 119 individuals with single or recurrent major depressive episodes, 128 individuals with bipolar disorder and a group of 346 controls were compared. There was a significant difference between patients with affective disorder and controls in the proportion of individuals carrying the STin2.9 allele. For the risk of unipolar disorder given a single STin2.9 allele, the odds ratio was 4.44 (95% Cl, 1.65-11.95) and for bipolar disorder 3.22 (95% Cl, 1.15-9.09). The findings support the hypothesis that allelic variation in the serotonin transporter gene may contribute to susceptibility for both major depression and bipolar disorder.

Alleles↗
PubMed1995

Control of a novel adenylyl cyclase by calcineurin.

The molecular complex formed by the immunosuppressant FK506 and the immunophilin protein FKBP12 potently inhibits the Ca2+/calmodulin-activated protein phosphatase calcineurin. This mechanism appears to be common to all types of cell, implying that fundamental physiological modes of calcineurin regulation are exploited by immunosuppressants. The present paper describes a novel adenylyl cyclase regulated by calcineurin that contains an FKBP12-like domain and may thus constitute a physiologically relevant calcineurin docking site mimicked by immunosuppressant-immunophilin complexes. The enzyme messenger RNA is particularly enriched in the cerebral cortex, striatum and hippocampus, where it is localized to neuronal perikarya, indicative of an important role in neuronal function.

Adenylyl Cyclases↗
PubMed1995

The distribution of vasoactive intestinal peptide2 receptor messenger RNA in the rat brain and pituitary gland as assessed by in situ hybridization.

The distribution of rat vasoactive intestinal peptide2 (VIP2) receptor messenger RNA in the brain and the pituitary gland was examined by in situ hybridization and by ribonuclease protection assay. labelled cells were found chiefly in the suprachiasmatic nucleus, the central nucleus of the amygdala and the thalamus (the lateral geniculate nucleus, and the paraventricular, mediodorsal and ventral nuclei of the thalamus). The distribution of the VIP2 receptor overlaps only in part with that of the VIP1 receptor, for example in the hippocampus, where VIP2 receptor messenger RNA was found in the pyramidal cells of the CA1-CA3 subfields and in the granule cells of the dentate gyrus. Small numbers of neurons containing high concentrations of VIP2 receptor messenger RNA were present in the brainstem in the principal sensory trigeminal nucleus and in the substantia gelatinosa of the spinal cord, suggesting a role for the VIP2 receptor in the processing of sensory information. The presence of the VIP2 receptor in the suprachiasmatic nucleus suggests that it is this receptor subtype which is involved in the control of circadian rhythms.

Animals↗
PubMed1994

The expression of the calcitonin receptor gene in the brain and pituitary gland of the rat.

The distribution of rat calcitonin receptor mRNA in the brain and pituitary gland were examined by in situ hybridization. Labelled cells were found in the nucleus accumbens, the preoptic and medial preoptic areas, the paraventricular nucleus of the hypothalamus, and the arcuate nucleus; a smaller number of cells were found in the brainstem and olfactory bulb. No strongly labelled cells were found in the pituitary gland.

Animals↗
PubMed1993

The VIP2 receptor: molecular characterisation of a cDNA encoding a novel receptor for vasoactive intestinal peptide.

We have cloned and sequenced a cDNA (RPR4) encoding a new member of the secretin/calcitonin/parathyroid hormone (PTH) receptor family. RPR4 was identified by PCR of rat pituitary cDNA, and a full-length clone was isolated from a rat olfactory bulb cDNA library. When RPR4 was functionally expressed in COS 7 cells, cyclic adenosine monophosphate (cAMP) production was stimulated by vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating peptides (PACAP-38 and PACAP-27) and helodermin, with equal potency. Peptide histidine isoleucine (PHI) and rat growth hormone releasing hormone (rGHRH) also stimulated cAMP production at lower potency. This suggests that RPR4 encodes a novel VIP receptor which we have designated the VIP2 receptor. In situ hybridisation showed that mRNA for this receptor was present mainly in the thalamus, hippocampus and in the suprachiasmatic nucleus.

Amino Acid Sequence↗
PubMed1993

Molecular cloning and expression of a cDNA encoding a receptor for pituitary adenylate cyclase activating polypeptide (PACAP).

We have cloned and sequenced a novel cDNA (RPR7) encoding a receptor for pituitary adenylate cyclase activating polypeptide (PACAP). RPR7 was identified by PCR of rat pituitary cDNA, and full-length clones were isolated from a rat olfactory bulb cDNA library. When expressed in COS cells, RPR7 was functionally coupled to increases in intracellular cyclic adenosine monophosphate (cAMP) in response to stimulation by PACAP-38, PACAP-27, vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI). The order of potency of these ligands was PACAP-38-PACAP-27 > VIP > PHI, suggesting that the receptor corresponds to the pharmacologically characterised PACAP Type I receptor.

Amino Acid Sequence↗