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D Julius

Publications and source records attributed to D Julius.

At least 37 records · Page 2Linked to original sources
PubMed1997

The capsaicin receptor: a heat-activated ion channel in the pain pathway.

Capsaicin, the main pungent ingredient in 'hot' chilli peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. We have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons. This receptor is a non-selective cation channel that is structurally related to members of the TRP family of ion channels. The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo.

Afferent Pathways↗
PubMed1996

ATP receptors in sickness, pain and death.

Extracellular ATP elicits biological responses ranging from cell death to synaptic transmission. Recent gene-cloning efforts have uncovered a family of cell-surface ATP receptors, which are potential targets for the development of novel drugs to treat airway and cardiovascular diseases, inflammation and pain.

Adenosine Triphosphate↗
PubMed1996

Signaling by extracellular nucleotides.

ATP and other nucleotides can be released from cells through regulated pathways, or following the loss of plasma membrane integrity. Once outside the cell, these compounds take on new roles as intercellular signaling molecules that elicit a broad spectrum of physiological responses through the activation of numerous cell surface receptor subtypes. This review summarizes recent advances in the molecular characterization of ATP receptors and discusses roles for cloned receptors in established and novel physiological processes.

Amino Acid Sequence↗
PubMed1995

Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors.

Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that is believed to modulate numerous sensory, motor and behavioural processes in the mammalian nervous system. These diverse responses are elicited through the activation of a large family of receptor subtypes. The complexity of this signalling system and the paucity of selective drugs have made it difficult to define specific roles for 5-HT receptor subtypes, or to determine how serotonergic drugs modulate mood and behaviour. To address these issues, we have generated mutant mice lacking functional 5-HT2C receptors (previously termed 5-HT1C), prominent G-protein-coupled receptors that are widely expressed throughout the brain and spinal cord and which have been proposed to mediate numerous central nervous system (CNS) actions of serotonin. Here we show that 5-HT2C receptor-deficient mice are overweight as a result of abnormal control of feeding behaviour, establishing a role for this receptor in the serotonergic control of appetite. Mutant animals are also prone to spontaneous death from seizures, suggesting that 5-HT2C receptors mediate tonic inhibition of neuronal network excitability.

Amino Acid Sequence↗
PubMed1995

Expression of a serotonin-gated ion channel in embryonic neural and nonneural tissues.

The neurotransmitter serotonin (5HT) has been implicated in morphogenesis of central nervous system and craniofacial structures. The actions of serotonin are mediated by multiple receptor subtypes, one of which, the 5HT3 receptor, is a ligand-gated ion channel. To determine whether this channel may contribute to the proposed morphogenic actions of serotonin, the expression of 5HT3 receptor transcripts was examined during mouse embryogenesis and correlated with the distribution of serotonin transporter mRNA and serotonin immunoreactivity. The pattern of 5HT3 receptor mRNA expression within the brain suggests possible roles for this receptor in the proliferation, differentiation, or migration of CNS neurons. In the peripheral nervous system, 5HT3 receptor transcripts were observed within cranial nerve sensory ganglia, olfactory neuroepithelia, and sympathoadrenal and enteric nervous systems during the initial stages of their formation. Striking expression of 5HT3 receptor transcripts occurred outside the nervous system, in association with regions of active chondrogenesis in the vertebral column, limbs, and craniofacial region, suggesting a possible involvement of this receptor subtype in the morphogenesis of olfactory receptor neurons, teeth, and genitalia.

Animals↗
PubMed1994

New structural motif for ligand-gated ion channels defined by an ionotropic ATP receptor.

The adenosine-5'-triphosphate (ATP) molecule is an extracellular messenger in neural and non-neural tissues, where it activates several cell-surface-receptor subtypes, including G-protein-coupled receptors and ligand-gated ion channels. ATP-gated channels (termed P2x receptors) have been characterized on smooth muscle cells and autonomic and sensory neurons, where they mediate membrane depolarization and, in some cases, Ca2+ entry. P2x receptors are functionally heterogeneous, but resemble acetylcholine- and serotonin-gated channels with respect to ion selectivity and kinetic parameters of channel gating. We report here that despite such close functional similarities, the deduced sequence of a cloned P2x receptor predicts an unusual subunit structure resembling voltage-insensitive cation channels. Thus, the P2x receptor provides a striking example of convergent evolution, whereby proteins have been fashioned with similar functional properties from subunits having very different structural characteristics. There is sequence similarity between the ATP receptor and RP-2, a gene activated in thymocytes undergoing programmed cell death. RP-2 may encode a receptor for ATP or another metabolite released during apoptosis.

Adenosine Triphosphate↗
PubMed1993

Expression cloning of an ATP receptor from mouse neuroblastoma cells.

Extracellular ATP activates cell-surface metabotropic and ionotropic nucleotide (P2) receptors in vascular, neural, connective, and immune tissues. These P2 receptors mediate a wealth of physiological processes, including nitric oxide-dependent vasodilation of vascular smooth muscle and fast excitatory neurotransmission in sensory afferents. Although ATP is now recognized as a signaling molecule, the cellular and molecular mechanisms underlying its actions have been difficult to study due to the absence of selective P2 receptor antagonists and cloned receptor genes. Nonetheless, five mammalian P2 receptor subtypes have been tentatively assigned based solely on agonist specificity and signaling properties. Here we report the cloning of a mouse cDNA encoding a P2 receptor that shares striking homology with several G protein-coupled peptide receptors. When expressed in Xenopus laevis oocytes, the cloned receptor resembles a metabotropic P2U receptor; activation by either ATP or UTP elicits the mobilization of intracellular calcium. mRNA encoding the P2U purinergic receptor is found in neural and nonneural tissues.

Adenosine Triphosphate↗
PubMed1993

Substitution of three amino acids switches receptor specificity of Gq alpha to that of Gi alpha.

Agonist-bound receptors activate heterotrimeric (alpha beta gamma) G proteins by catalysing replacement of GDP bound to the alpha-subunit by GTP. mutations in the C terminus of the alpha-subunit, its covalent modification by pertussis toxin-catalysed ribosylation of ADP, peptide-specific antibodies directed against it, and peptides mimicking C-terminal sequences, all inhibit receptor-mediated activation of G proteins. The logical prediction--that specific amino-acid residues at the C-termini of alpha-subunits can determine the abilities of individual G proteins to discriminate among specific subsets of receptors--has so far not been tested experimentally. Different hormone receptors specifically activate Gq or Gi, whose alpha-subunits (alpha q or alpha i) stimulate phosphatidylinositol-specific phospholipase C or inhibit adenylyl cyclase, respectively. Here we replace C-terminal amino acids of alpha q with the corresponding residues of alpha i2 to create alpha q/alpha i2 chimaeras that can mediate stimulation of phospholipase C by receptors otherwise coupled exclusively to Gi. A minimum of three alpha i2 amino acids, including a glycine three residues from the C terminus, suffices to switch the receptor specificity of the alpha q/alpha i2 chimaeras. We propose that a C-terminal turn, centered on this glycine, plays an important part in specifying receptor interactions of G proteins in the Gi/Go/Gz family.

Adenylate Cyclase Toxin↗
PubMed1993

Nervous system distribution of the serotonin 5-HT3 receptor mRNA.

The serotonin 5-HT3 receptor subtype has been implicated in many brain functions. Antagonists of this receptor have anxiolytic and antiemetic effects in humans and in animal models. To determine with cellular resolution the distribution of 5-HT3 receptor mRNA, in situ hybridization was performed in sections of mouse brain and dorsal root ganglia. Scattered labeled cells were observed throughout cortical regions, with highest densities in the piriform, cingulate, and entorhinal areas. Strong hybridization signals were seen in the hippocampal formation, where expression appeared primarily in interneurons. Labeled cells were most abundant in the posteroventral hippocampal region, particularly in the lacunosum moleculare layer of CA1. This distribution suggests that 5-HT3 receptors may mediate the known serotonergic inhibition of pyramidal cell populations via excitation of inhibitory interneurons. Labeled cells were also observed in the major subdivisions of the amygdaloid complex, the olfactory bulb, the trochlear nerve nucleus, the dorsal tegmental region, the facial nerve nucleus, the nucleus of the spinal tract of the trigeminal nerve, and the spinal cord dorsal horn. In the periphery, intense hybridization signals were seen in a subpopulation of cells in dorsal root ganglia. The data correlate generally with physiological, behavioral, and receptor autoradiographic studies, provide cellular resolution, and reveal regions of receptor expression not previously observed. The distribution of 5-HT3 receptor mRNA is consistent with roles for the receptor in cognition and affect and in the modulation of sensory input.

Amygdala↗
PubMed1993

A new wave of serotonin receptors.

The neurotransmitter serotonin mediates diverse effects through multiple receptor subtypes. Recently, many of these receptor subtypes have been identified, molecularly cloned and characterized, advancing our understanding of their functional roles in the central and peripheral nervous systems.

Animals↗
PubMed1992

Effects of 5-HT1C-receptor expression on cell proliferation control in hamster fibroblasts: serotonin fails to induce a transformed phenotype.

5-HT1c receptors have been shown to act as protooncogenes in NIH 3T3 cells, inducing ligand-dependent focus formation. In order to assess their mitogenic and oncogenic potential in a different cell system, we transfected these receptors into CCL39 hamster fibroblasts, a well-characterized growth factor-dependent cell line. Cell clones expressing functional receptors were isolated and tested for (a) growth factor dependence of proliferation measuring thymidine incorporation in response to varying doses of serum, (b) the response to serotonin alone or in combination with other growth factors, and (c) the capacity for anchorage-independent proliferation. In the absence or presence of serotonin, the large majority of the clones isolated showed normal morphology and normal growth factor dependence and was unable to grow in soft agar. None of the clones showed a significant response to serotonin alone in DNA synthesis reinitiation experiments, but synergy was observed between serotonin and the tyrosine kinase activating growth factors EGF and FGF. However, the major part of this effect could be abolished by an antagonist of 5-HT1b receptors, which are endogenous in CCL39 cells. The same receptor was found to mediate a significant mitogenic response to the neurotransmitter in Ha-ras-transfected cells. The fact that 5-HT1c receptors do not readily induce a transformed phenotype in CCL39 cells clearly distinguishes them from strong dominantly acting oncogene products like RAS, SRC, or FMS.

Animals↗
PubMed1992

Serotonin receptor 1c gene assigned to X chromosome in human (band q24) and mouse (bands D-F4).

In the mammalian nervous system, serotonin (5-hydroxytryptamine) binds to distinct cell surface receptor subtypes that are defined by their ligand binding and effector-coupling properties. The 5HT1c receptor is a G-protein coupled receptor that stimulates phospholipase C-catalyzed hydrolysis of phosphatidylinositol bisphosphate, leading to the mobilization of intracellular calcium and to the activation of protein kinase C. By using somatic cell hybrid analysis and FISH, we have mapped the HTR1C locus to the human X chromosome, band q24 and to the mouse X chromosome region D-F4. Comparison of these map positions offers new insights into the evolution of human and murine X chromosomes. Since HTR1C is expressed in certain parts of the central nervous system and abnormal function of the serotoninergic system has been implicated in affective disorders, obsessive-compulsive disorder and epilepsy, establishing the precise map position of HTR1C is an important first step toward evaluating this locus as a candidate for mutations in these syndromes and in X-linked mental disorders.

Animals↗
PubMed1991

Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel.

The neurotransmitter serotonin (5HT) activates a variety of second messenger signaling systems and through them indirectly regulates the function of ion channels. Serotonin also activates ion channels directly, suggesting that it may also mediate rapid, excitatory responses. A complementary DNA clone containing the coding sequence of one of these rapidly responding channels, a 5HT3 subtype of the serotonin receptor, has been isolated by screening a neuroblastoma expression library for functional expression of serotonin-gated currents in Xenopus oocytes. The predicted protein product has many of the features shared by other members of the ligand-gated ion channel family. The pharmacological and electrophysiological characteristics of the cloned receptor are largely consistent with the properties of native 5HT3 receptors. Messenger RNA encoding this receptor is found in the brain, spinal cord, and heart. This receptor defines a new class of excitatory ligand-gated channels.

Amino Acid Sequence↗
PubMed1990

The serotonin receptor subtype 2 locus HTR2 is on human chromosome 13 near genes for esterase D and retinoblastoma-1 and on mouse chromosome 14.

Serotonin (5-hydroxytryptamine) functions as a neurotransmitter and a hormone. Its diverse actions are mediated by at least seven distinct cell surface receptor subtypes. The serotonin receptor subtype 2 (gene symbol HTR2) is a G-protein-coupled receptor, expressed primarily in the cerebral cortex, where upon stimulation it stimulates the hydrolysis of inositol phospholipids. We have mapped the HTR2 locus to human chromosome 13 and to mouse chromosome 14 by somatic cell hybrid analysis. Linkage studies in CEPH families, using a PvuII RFLP detected with the HTR2 probe, revealed tight linkage between HTR2 and ESD, the locus for esterase D. The most likely position for HTR2 is between ESD and RB1, the retinoblastoma-1 gene. The homologous loci in mouse, Rb-1 and Esd(Es-10) are on mouse chromosome 14, close to ag, agitans, a recessive neurological mutation. Having mapped Htr-2 to mouse chromosome 14, we predict that it falls into this known conserved gene cluster.

Animals↗
PubMed1990

The 5HT2 receptor defines a family of structurally distinct but functionally conserved serotonin receptors.

Serotonin exerts its diverse physiological effects by interacting with multiple distinct receptor subtypes. We have isolated a rat brain 5HT2 serotonin receptor cDNA by virtue of its homology with the 5HT1c receptor. The 5HT2 receptor is a member of the family of receptors that are linked to guanine nucleotide-binding proteins and are predicted to span the lipid bilayer seven times. Overall sequence identity between the 5HT2 and 5HT1c receptors is 49%, but identity within the transmembrane domains is 80%. Expression of both the 5HT2 and 5HT1c receptors in transfected mouse fibroblasts activates phospholipase C signaling pathways and promotes cellular transformation. However, RNA blotting shows that these two receptor subtypes are differentially expressed in the central nervous system. In this manner, structurally and functionally homologous receptor subtypes may elicit distinct physiologic actions.

Amino Acid Sequence↗