Bio

Clinical Focus


  • Neurology

Academic Appointments


Honors & Awards


  • Medical Science Scholar Award, Charles E. Culpeper Foundation (1998-2002)
  • Rober H. Ebert Clinical Scholar, Klingenstein Foundation (1998-2001)
  • Klingenstein Award, Klingenstein Foundation (1998-2001)
  • Basil O'Connor Award, March of Dimes (1997-1999)
  • Clinical Investigator Development Award, NINDS (1996-2001)
  • MSTP Scholar, Harvard Medical School (1984-1992)
  • Frank Knox Memorial Fellow, Harvard Medical School (1985-1986)
  • Carl Walter Memorial Fellow, Harvard Medical School (1984-1985)
  • Honors, Stanford University, Biology (1982)

Professional Education


  • Residency:University of California School of Medicine (1996) CA
  • Board Certification: Neurology, American Board of Psychiatry and Neurology (1998)
  • Internship:The Malden Hospital (1993) MA
  • Medical Education:Harvard Medical School (1992) MA
  • Board Certification, American Board of Psychiatry and Neurology, Neurology (1998)
  • Residency, UCSF Medical Center, Neurology (1996)
  • Internship, Malden Hospital, Medicine (1993)
  • Medical Education, Harvard Medical School (1992)
  • Ph.D., Harvard Medical School, Neuroscience (1992)
  • MS, Stanford University, Biology (1982)
  • BS, Stanford University, Biology (1981)

Publications

Journal Articles


  • A Caenorhabditis elegans p38 MAP kinase pathway mutant protects from dopamine, methamphetamine, and MDMA toxicity NEUROSCIENCE LETTERS Schreiber, M. A., McIntire, S. L. 2011; 498 (1): 99-103

    Abstract

    Biogenic amine systems are damaged by amphetamine abuse and in Parkinson's disease. The mechanisms mediating this damage are of high importance because of the public health impact of these problems. Here we have taken advantage of the Caenorhabditis elegans nematode model system to investigate genetic modifiers of biogenic amine toxicity. In a forward genetic screen, we identified a mutant resistant to the toxic effects of dopamine. This mutant was also resistant to toxic doses of methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA). In addition, this mutation conferred resistance to 6-hydroxydopamine damage to dopaminergic neurons in a Parkinson's disease model. Resistance was due to a mutation in the nsy-1 gene, orthologous to the mammalian ASK-1 MAPKKK. NSY-1 is in the highly conserved p38 MAP kinase pathway, which plays a crucial role in C. elegans innate immunity, suggesting that this pathway may play a role in biogenic amine toxicity system damage due to amphetamines and in the pathogenesis of Parkinson's disease in higher organisms.

    View details for DOI 10.1016/j.neulet.2011.04.071

    View details for Web of Science ID 000292404600021

    View details for PubMedID 21565252

  • A Novel zf-MYND Protein, CHB-3, Mediates Guanylyl Cyclase Localization to Sensory Cilia and Controls Body Size of Caenorhabditis elegans PLOS GENETICS Fujiwara, M., Teramoto, T., Ishihara, T., Ohshima, Y., McIntire, S. L. 2010; 6 (11)

    Abstract

    Cilia are important sensory organelles, which are thought to be essential regulators of numerous signaling pathways. In Caenorhabditis elegans, defects in sensory cilium formation result in a small-body phenotype, suggesting the role of sensory cilia in body size determination. Previous analyses suggest that lack of normal cilia causes the small-body phenotype through the activation of a signaling pathway which consists of the EGL-4 cGMP-dependent protein kinase and the GCY-12 receptor-type guanylyl cyclase. By genetic suppressor screening of the small-body phenotype of a cilium defective mutant, we identified a chb-3 gene. Genetic analyses placed chb-3 in the same pathway as egl-4 and gcy-12 and upstream of egl-4. chb-3 encodes a novel protein, with a zf-MYND motif and ankyrin repeats, that is highly conserved from worm to human. In chb-3 mutants, GCY-12 guanylyl cyclase visualized by tagged GFP (GCY-12::GFP) fails to localize to sensory cilia properly and accumulates in cell bodies. Our analyses suggest that decreased GCY-12 levels in the cilia of chb-3 mutants may cause the suppression of the small-body phenotype of a cilium defective mutant. By observing the transport of GCY-12::GFP particles along the dendrites to the cilia in sensory neurons, we found that the velocities and the frequencies of the particle movement are decreased in chb-3 mutant animals. How membrane proteins are trafficked to cilia has been the focus of extensive studies in vertebrates and invertebrates, although only a few of the relevant proteins have been identified. Our study defines a new regulator, CHB-3, in the trafficking process and also shows the importance of ciliary targeting of the signaling molecule, GCY-12, in sensory-dependent body size regulation in C. elegans. Given that CHB-3 is highly conserved in mammal, a similar system may be used in the trafficking of signaling proteins to the cilia of other species.

    View details for DOI 10.1371/journal.pgen.1001211

    View details for Web of Science ID 000284587100025

    View details for PubMedID 21124861

  • Conserved Role of unc-79 in Ethanol Responses in Lightweight Mutant Mice PLOS GENETICS Speca, D. J., Chihara, D., Ashique, A. M., Bowers, M. S., Pierce-Shimomura, J. T., Lee, J., Rabbee, N., Speed, T. P., Gularte, R. J., Chitwood, J., Medrano, J. F., Liao, M., Sonner, J. M., Eger, E. I., Peterson, A. S., McIntire, S. L. 2010; 6 (8)

    Abstract

    The mechanisms by which ethanol and inhaled anesthetics influence the nervous system are poorly understood. Here we describe the positional cloning and characterization of a new mouse mutation isolated in an N-ethyl-N-nitrosourea (ENU) forward mutagenesis screen for animals with enhanced locomotor activity. This allele, Lightweight (Lwt), disrupts the homolog of the Caenorhabditis elegans (C. elegans) unc-79 gene. While Lwt/Lwt homozygotes are perinatal lethal, Lightweight heterozygotes are dramatically hypersensitive to acute ethanol exposure. Experiments in C. elegans demonstrate a conserved hypersensitivity to ethanol in unc-79 mutants and extend this observation to the related unc-80 mutant and nca-1;nca-2 double mutants. Lightweight heterozygotes also exhibit an altered response to the anesthetic isoflurane, reminiscent of unc-79 invertebrate mutant phenotypes. Consistent with our initial mapping results, Lightweight heterozygotes are mildly hyperactive when exposed to a novel environment and are smaller than wild-type animals. In addition, Lightweight heterozygotes exhibit increased food consumption yet have a leaner body composition. Interestingly, Lightweight heterozygotes voluntarily consume more ethanol than wild-type littermates. The acute hypersensitivity to and increased voluntary consumption of ethanol observed in Lightweight heterozygous mice in combination with the observed hypersensitivity to ethanol in C. elegans unc-79, unc-80, and nca-1;nca-2 double mutants suggests a novel conserved pathway that might influence alcohol-related behaviors in humans.

    View details for DOI 10.1371/journal.pgen.1001057

    View details for Web of Science ID 000281383800013

    View details for PubMedID 20714347

  • Manipulation of Behavioral Decline in Caenorhabditis elegans with the Rag GTPase raga-1 PLOS GENETICS Schreiber, M. A., Pierce-Shimomura, J. T., Chan, S., Parry, D., McIntire, S. L. 2010; 6 (5)

    Abstract

    Normal aging leads to an inexorable decline in motor performance, contributing to medical morbidity and decreased quality of life. While much has been discovered about genetic determinants of lifespan, less is known about modifiers of age-related behavioral decline and whether new gene targets may be found which extend vigorous activity, with or without extending lifespan. Using Caenorhabditis elegans, we have developed a model of declining neuromuscular function and conducted a screen for increased behavioral activity in aged animals. In this model, behavioral function suffers from profound reductions in locomotory frequency, but coordination is strikingly preserved until very old age. By screening for enhancers of locomotion at advanced ages we identified the ras-related Rag GTPase raga-1 as a novel modifier of behavioral aging. raga-1 loss of function mutants showed vigorous swimming late in life. Genetic manipulations revealed that a gain of function raga-1 curtailed behavioral vitality and shortened lifespan, while a dominant negative raga-1 lengthened lifespan. Dietary restriction results indicated that a raga-1 mutant is relatively protected from the life-shortening effects of highly concentrated food, while RNAi experiments suggested that raga-1 acts in the highly conserved target of rapamycin (TOR) pathway in C. elegans. Rag GTPases were recently shown to mediate nutrient-dependent activation of TOR. This is the first demonstration of their dramatic effects on behavior and aging. This work indicates that novel modulators of behavioral function can be identified in screens, with implications for future study of the clinical amelioration of age-related decline.

    View details for DOI 10.1371/journal.pgen.1000972

    View details for Web of Science ID 000278557300041

    View details for PubMedID 20523893

  • Ethanol. WormBook : the online review of C. elegans biology McIntire, S. L. 2010: 1-6

    Abstract

    Ethanol is a widely used drug whose mechanism of action, despite intensive study, remains uncertain. Biochemical and electrophysiological experiments have identified receptors and ion channels whose functions are altered at physiological concentrations of ethanol. Yet, the contribution of these potential targets to its intoxicating or behavioral effects is unclear. Unbiased forward genetic screens for resistant or hypersensitive mutants represent an attractive means of identifying the relevant molecular targets or biochemical pathways mediating the behavioral effects of neuroactive compounds. C. elegans has proven to be a particularly useful system for such studies. The behavioral effects of ethanol occur at equivalent tissue concentrations in mammals and in C. elegans, suggesting the existence of conserved drug targets in the nervous system. This chapter reviews the results of studies directed toward determining the mechanisms of action of ethanol. Studies of the neural adaptations that occur with prolonged drug exposure are also discussed. The methods used to characterize the actions of ethanol should be applicable to the characterizations of other compounds that affect the behavior of C. elegans.

    View details for DOI 10.1895/wormbook.1.40.1

    View details for PubMedID 20432508

  • The Dystrophin Complex Controls BK Channel Localization and Muscle Activity in Caenorhabditis elegans PLOS GENETICS Kim, H., Pierce-Shimomura, J. T., Oh, H. J., Johnson, B. E., Goodman, M. B., McIntire, S. L. 2009; 5 (12)

    Abstract

    Genetic defects in the dystrophin-associated protein complex (DAPC) are responsible for a variety of pathological conditions including muscular dystrophy, cardiomyopathy, and vasospasm. Conserved DAPC components from humans to Caenorhabditis elegans suggest a similar molecular function. C. elegans DAPC mutants exhibit a unique locomotory deficit resulting from prolonged muscle excitation and contraction. Here we show that the C. elegans DAPC is essential for proper localization of SLO-1, the large conductance, voltage-, and calcium-dependent potassium (BK) channel, which conducts a major outward rectifying current in muscle under the normal physiological condition. Through analysis of mutants with the same phenotype as the DAPC mutants, we identified the novel islo-1 gene that encodes a protein with two predicted transmembrane domains. We demonstrate that ISLO-1 acts as a novel adapter molecule that links the DAPC to SLO-1 in muscle. We show that a defect in either the DAPC or ISLO-1 disrupts normal SLO-1 localization in muscle. Consistent with observations that SLO-1 requires a high calcium concentration for full activation, we find that SLO-1 is localized near L-type calcium channels in muscle, thereby providing a mechanism coupling calcium influx with the outward rectifying current. Our results indicate that the DAPC modulates muscle excitability by localizing the SLO-1 channel to calcium-rich regions of C. elegans muscle.

    View details for DOI 10.1371/journal.pgen.1000780

    View details for Web of Science ID 000273469700030

    View details for PubMedID 20019812

  • Ethanol preference in C-elegans GENES BRAIN AND BEHAVIOR Lee, J., Jee, C., McIntire, S. L. 2009; 8 (6): 578-585

    Abstract

    Caenorhabditis elegans senses multiple environmental stimuli through sensory systems and rapidly changes its behaviors for survival. With a simple and well-characterized nervous system, C. elegans is a suitable animal model for studying behavioral plasticity. Previous studies have shown acute neurodepressive effects of ethanol on multiple behaviors of C. elegans similar to the effect of ethanol on other organisms. Caenorhabditis elegans also develops ethanol tolerance during continuous exposure to ethanol. In mammals, chronic ethanol exposure leads to ethanol tolerance as well as increased ethanol consumption. Ethanol preference is associated with the development of tolerance and may lead to the development of ethanol dependence. In this study, we show that C. elegans is a useful model organism for studying chronic effects of ethanol, including the development of ethanol preference. We designed a behavioral assay for testing ethanol preference after prolonged ethanol exposure. Despite baseline aversive responses to ethanol, animals show ethanol preference after 4 h of pre-exposure to ethanol and exhibit significantly enhanced preference for ethanol after a lifetime of ethanol exposure. The cat-2 and tph-1 mutant animals have defects in the synthetic enzymes for dopamine and serotonin, respectively. These mutants are deficient in the development of ethanol preference, indicating that dopamine and serotonin are required for this form of behavioral plasticity.

    View details for DOI 10.1111/j.1601-183X.2009.00513.x

    View details for Web of Science ID 000268655200002

    View details for PubMedID 19614755

  • Genetic analysis of crawling and swimming locomotory patterns in C. elegans PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Pierce-Shimomura, J. T., Chen, B. L., Mun, J. J., Ho, R., Sarkis, R., McIntire, S. L. 2008; 105 (52): 20982-20987

    Abstract

    Alternative patterns of neural activity drive different rhythmic locomotory patterns in both invertebrates and mammals. The neuro-molecular mechanisms responsible for the expression of rhythmic behavioral patterns are poorly understood. Here we show that Caenorhabditis elegans switches between distinct forms of locomotion, or crawling versus swimming, when transitioning between solid and liquid environments. These forms of locomotion are distinguished by distinct kinematics and different underlying patterns of neuromuscular activity, as determined by in vivo calcium imaging. The expression of swimming versus crawling rhythms is regulated by sensory input. In a screen for mutants that are defective in transitioning between crawl and swim behavior, we identified unc-79 and unc-80, two mutants known to be defective in NCA ion channel stabilization. Genetic and behavioral analyses suggest that the NCA channels enable the transition to rapid rhythmic behaviors in C. elegans. unc-79, unc-80, and the NCA channels represent a conserved set of genes critical for behavioral pattern generation.

    View details for DOI 10.1073/pnas.0810359105

    View details for Web of Science ID 000262092800074

    View details for PubMedID 19074276

  • Loss of RAB-3/A in Caenorhabditis elegans and the mouse affects behavioral response to ethanol GENES BRAIN AND BEHAVIOR Kapfhamer, D., Bettinger, J. C., Davies, A. G., Eastman, C. L., Smail, E. A., Heberlein, U., McIntire, S. L. 2008; 7 (6): 669-676

    Abstract

    The mechanisms by which ethanol induces changes in behavior are not well understood. Here, we show that Caenorhabditis elegans loss-of-function mutations in the synaptic vesicle-associated RAB-3 protein and its guanosine triphosphate exchange factor AEX-3 confer resistance to the acute locomotor effects of ethanol. Similarly, mice lacking one or both copies of Rab3A are resistant to the ataxic and sedative effects of ethanol, and Rab3A haploinsufficiency increases voluntary ethanol consumption. These data suggest a conserved role of RAB-3-/RAB3A-regulated neurotransmitter release in ethanol-related behaviors.

    View details for DOI 10.1111/j.1601-183X.2008.00404.x

    View details for Web of Science ID 000258209600007

    View details for PubMedID 18397381

  • The G-protein-coupled serotonin receptor SER-1 regulates egg laying and male mating behaviors in Caenorhabditis elegans JOURNAL OF NEUROSCIENCE Carnell, L., Illi, J., Hong, S. W., McIntire, S. L. 2005; 25 (46): 10671-10681

    Abstract

    Serotonin (5-HT) is a neuromodulator that regulates many aspects of animal behavior, including mood, aggression, sex drive, and sleep. In vertebrates, most of the behavioral effects of 5-HT appear to be mediated by G-protein-coupled receptors (GPCRs). Here, we show that SER-1 is the 5-HT GPCR responsible for the stimulatory effects of exogenous 5-HT in two sexually dimorphic behaviors of Caenorhabditis elegans, egg laying and male ventral tail curling. Loss of ser-1 function leads to decreased egg laying in hermaphrodites and defects in the turning step of mating behavior in males. ser-1 is expressed in muscles that are postsynaptic to serotonergic neurons and are known to be required for these behaviors. Analysis of the ser-1 mutant also reveals an inhibitory effect of 5-HT on egg laying that is normally masked by SER-1-dependent stimulation. This inhibition of egg laying requires MOD-1, a 5-HT-gated chloride channel. Loss of mod-1 function in males also produces defects in ventral tail curling and enhances the turning defects in ser-1 mutant males. Sustained elevations in 5-HT levels result in behavioral adaptation to both the stimulatory and inhibitory actions of the neurotransmitter, indicating that both SER-1 and MOD-1 signaling can be modulated. Removal of wild-type animals from high levels of exogenous 5-HT produces a SER-1-dependent withdrawal response in which egg laying is significantly decreased. These studies provide insight into the role of 5-HT in behavior and the regulation of 5-HT(2) receptor function.

    View details for DOI 10.1523/JNEUROSCI.3399-05.2005

    View details for Web of Science ID 000233319100011

    View details for PubMedID 16291940

  • State-dependancy in C-elegans GENES BRAIN AND BEHAVIOR Bettinger, J. C., McIntire, S. L. 2004; 3 (5): 266-272

    Abstract

    Memory and the expression of learned behaviors by an organism are often triggered by contextual cues that resemble those that were present when the initial learning occurred. In state-dependent learning, the cue eliciting a learned behavior is a neuroactive drug; behaviors initially learned during exposure to centrally acting compounds such as ethanol are subsequently recalled better if the drug stimulus is again present during testing. Although state-dependent learning is well documented in many vertebrate systems, the molecular mechanisms underlying state-dependent learning and other forms of contextual learning are not understood. Here we demonstrate and present a genetic analysis of state- dependent adaptation in Caenorhabditis elegans. C. elegans normally exhibits adaptation, or reduced behavioral response, to an olfactory stimulus after prior exposure to the stimulus. If the adaptation to the olfactory stimulus is acquired during ethanol administration, the adaptation is subsequently displayed only if the ethanol stimulus is again present. cat-1 and cat-2 mutant animals are defective in dopaminergic neuron signaling and are impaired in state dependency, indicating that dopamine functions in state-dependent adaptation in C. elegans.

    View details for Web of Science ID 000223988600002

    View details for PubMedID 15344920

  • SNF-6 is an acetylcholine transporter interacting with the dystrophin complex in Caenorhabditis elegans NATURE Kim, H., Rogers, M. J., Richmond, J. E., McIntire, S. L. 2004; 430 (7002): 891-896

    Abstract

    Muscular dystrophies are among the most common human genetic diseases and are characterized by progressive muscle degeneration. Muscular dystrophies result from genetic defects in components of the dystrophin-glycoprotein complex (DGC), a multimeric complex found in the muscle cell plasma membrane. The DGC links the intracellular cytoskeleton to the extracellular matrix and is thought to be important for maintaining the mechanical integrity of muscles and organizing signalling molecules. The exact role of the DGC in the pathogenesis of disease has, however, remained uncertain. Mutations in Caenorhabditis elegans DGC genes lead to specific defects in coordinated movement and can also cause muscle degeneration. Here we show that mutations in the gene snf-6 result in phenotypes indistinguishable from those of the DGC mutants, and that snf-6 encodes a novel acetylcholine/choline transporter. SNF-6 mediates the uptake of acetylcholine at neuromuscular junctions during periods of increased synaptic activity. SNF-6 also interacts with the DGC, and mutations in DGC genes cause a loss of SNF-6 at neuromuscular junctions. Improper clearing of acetylcholine and prolonged excitation of muscles might contribute to the pathogenesis of muscular dystrophies.

    View details for DOI 10.1038/nature02798

    View details for Web of Science ID 000223369800042

    View details for PubMedID 15318222

  • Natural variation in the npr-1 gene modifies ethanol responses of wild strains of C. elegans NEURON Davies, A. G., Bettinger, J. C., Thiele, T. R., Judy, M. E., McIntire, S. L. 2004; 42 (5): 731-743

    Abstract

    Variation in the acute response to ethanol between individuals has a significant impact on determining susceptibility to alcoholism. The degree to which genetics contributes to this variation is of great interest. Here we show that allelic variation that alters the functional level of NPR-1, a neuropeptide Y (NPY) receptor-like protein, can account for natural variation in the acute response to ethanol in wild strains of Caenorhabditis elegans. NPR-1 negatively regulates the development of acute tolerance to ethanol, a neuroadaptive process that compensates for effects of ethanol. Furthermore, dynamic changes in the NPR-1 pathway provide a mechanism for ethanol tolerance in C. elegans. This suggests an explanation for the conserved function of NPY-related pathways in ethanol responses across diverse species. Moreover, these data indicate that genetic variation in the level of NPR-1 function determines much of the phenotypic variation in adaptive behavioral responses to ethanol that are observed in natural populations.

    View details for Web of Science ID 000221975000006

    View details for PubMedID 15182714

  • Using C. elegans to screen for targets of ethanol and behavior-altering drugs. Biological procedures online Davies, A. G., McIntire, S. L. 2004; 6: 113-119

    Abstract

    Caenorhabditis elegans is an attractive model system for determining the targets of neuroactive compounds. Genetic screens in C. elegans provide a relatively unbiased approach to the identification of genes that are essential for behavioral effects of drugs and neuroactive compounds such as alcohol. Much work in vertebrate systems has identified multiple potential targets of ethanol but which, if any, of those candidates are responsible for the behavioral effects of alcohol is uncertain. Here we provide detailed methodology for a genetic screen for mutants of C. elegans that are resistant to the depressive effects of ethanol on locomotion and for the subsequent behavioral analysis of those mutants. The methods we describe should also be applicable for use in screening for mutants that are resistant or hypersensitive to many neuroactive compounds and for identifying the molecular targets or biochemical pathways mediating drug responses.

    View details for PubMedID 15192754

  • The use of Caenorhabditis elegans in molecular neuropharmacology INTERNATIONAL REVIEW OF NEUROBIOLOGY, VOL 62 Bellinger, J. C., Carnell, L., Davies, A. G., McIntire, S. L. 2004; 62: 195-212

    View details for Web of Science ID 000225608200007

    View details for PubMedID 15530573

  • A central role of the BK potassium channel in behavioral responses to ethanol in C-elegans CELL Davies, A. G., Pierce-Shimomura, J. T., Kim, H., VanHoven, M. K., Thiele, T. R., Bonci, A., Bargmann, C. I., McIntire, S. L. 2003; 115 (6): 655-666

    Abstract

    The activities of many neuronal proteins are modulated by ethanol, but the fundamental mechanisms underlying behavioral effects of ethanol remain unclear. To identify mechanisms responsible for intoxication, we screened for Caenorhabditis elegans mutants with altered behavioral responses to ethanol. We found that slo-1 mutants, which were previously recognized as having slightly uncoordinated movement, are highly resistant to ethanol in two behavioral assays. Numerous loss-of-function slo-1 alleles emerged from our screens, indicating that slo-1 has a central role in ethanol responses. slo-1 encodes the BK potassium channel. Electrophysiological analysis shows that ethanol activates the channel in vivo, which would inhibit neuronal activity. Moreover, behaviors of slo-1 gain-of-function mutants resemble those of ethanol-intoxicated animals. These results demonstrate that selective activation of BK channels is responsible for acute intoxicating effects of ethanol in C. elegans. BK channel activation may explain a variety of behavioral responses to ethanol in invertebrate and vertebrate systems.

    View details for Web of Science ID 000187366100006

    View details for PubMedID 14675531

  • Regulation of body size and behavioral state of C-elegans by sensory perception and the EGL-4 cGMP-dependent protein kinase NEURON Fujiwara, M., Sengupta, P., McIntire, S. L. 2002; 36 (6): 1091-1102

    Abstract

    The growth and behavior of higher organisms depend on the accurate perception and integration of sensory stimuli by the nervous system. We show that defects in sensory perception in C. elegans result in abnormalities in the growth of the animal and in the expression of alternative behavioral states. Our analysis suggests that sensory neurons modulate neural or neuroendocrine functions, regulating both bodily growth and behavioral state. We identify genes likely to be required for these functions downstream of sensory inputs. Here, we characterize one of these genes as egl-4, which we show encodes a cGMP-dependent protein kinase. We demonstrate that this cGMP-dependent kinase functions in neurons of C. elegans to regulate multiple developmental and behavioral processes including the orchestrated growth of the animal and the expression of particular behavioral states.

    View details for Web of Science ID 000180011600012

    View details for PubMedID 12495624

  • A family of yeast proteins mediating bidirectional vacuolar amino acid transport JOURNAL OF BIOLOGICAL CHEMISTRY Russnak, R., Konczal, D., McIntire, S. L. 2001; 276 (26): 23849-23857

    Abstract

    Seven genes in Saccharomyces cerevisiae are predicted to code for membrane-spanning proteins (designated AVT1-7) that are related to the neuronal gamma-aminobutyric acid-glycine vesicular transporters. We have now demonstrated that four of these proteins mediate amino acid transport in vacuoles. One protein, AVT1, is required for the vacuolar uptake of large neutral amino acids including tyrosine, glutamine, asparagine, isoleucine, and leucine. Three proteins, AVT3, AVT4, and AVT6, are involved in amino acid efflux from the vacuole and, as such, are the first to be shown directly to transport compounds from the lumen of an acidic intracellular organelle. This function is consistent with the role of the vacuole in protein degradation, whereby accumulated amino acids are exported to the cytosol. Protein AVT6 is responsible for the efflux of aspartate and glutamate, an activity that would account for their exclusion from vacuoles in vivo. Transport by AVT1 and AVT6 requires ATP for function and is abolished in the presence of nigericin, indicating that the same pH gradient can drive amino acid transport in opposing directions. Efflux of tyrosine and other large neutral amino acids by the two closely related proteins, AVT3 and AVT4, is similar in terms of substrate specificity to transport system h described in mammalian lysosomes and melanosomes. These findings suggest that yeast AVT transporter function has been conserved to control amino acid flux in vacuolar-like organelles.

    View details for Web of Science ID 000169531100084

    View details for PubMedID 11274162

  • Identification and characterization of the vesicular GABA transporter NATURE McIntire, S. L., Reimer, R. J., Schuske, K., Edwards, R. H., Jorgensen, E. M. 1997; 389 (6653): 870-876

    Abstract

    Synaptic transmission involves the regulated exocytosis of vesicles filled with neurotransmitter. Classical transmitters are synthesized in the cytoplasm, and so must be transported into synaptic vesicles. Although the vesicular transporters for monoamines and acetylcholine have been identified, the proteins responsible for packaging the primary inhibitory and excitatory transmitters, gamma-aminobutyric acid (GABA) and glutamate remain unknown. Studies in the nematode Caenorhabditis elegans have implicated the gene unc-47 in the release of GABA. Here we show that the sequence of unc-47 predicts a protein with ten transmembrane domains, that the gene is expressed by GABA neurons, and that the protein colocalizes with synaptic vesicles. Further, a rat homologue of unc-47 is expressed by central GABA neurons and confers vesicular GABA transport in transfected cells with kinetics and substrate specificity similar to those previously reported for synaptic vesicles from the brain. Comparison of this vesicular GABA transporter (VGAT) with a vesicular transporter for monoamines shows that there are differences in the bioenergetic dependence of transport, and these presumably account for the differences in structure. Thus VGAT is the first of a new family of neurotransmitter transporters.

    View details for Web of Science ID A1997YC14800062

    View details for PubMedID 9349821

  • THE GABAERGIC NERVOUS-SYSTEM OF CAENORHABDITIS-ELEGANS NATURE McIntire, S. L., Jorgensen, E., Kaplan, J., Horvitz, H. R. 1993; 364 (6435): 337-341

    Abstract

    gamma-Aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in vertebrates and invertebrates. GABA receptors are the target of anxiolytic, antiepileptic and antispasmodic drugs, as well as of commonly used insecticides. How does a specific neurotransmitter such as GABA control animal behaviour? To answer this question, we identified all neurons that react with antisera raised against the neurotransmitter GABA in the nervous system of the nematode Caenorhabditis elegans. We determined the in vivo functions of 25 of the 26 GABAergic neurons by killing these cells with a laser microbeam in living animals and by characterizing a mutant defective in GABA expression. On the basis of the ultrastructurally defined connectivity of the C. elegans nervous system, we deduced how these GABAergic neurons act to control the body and enteric muscles necessary for different behaviours. Our findings provide evidence that GABA functions as an excitatory as well as an inhibitory neurotransmitter.

    View details for Web of Science ID A1993LN57000057

    View details for PubMedID 8332191

  • GENES REQUIRED FOR GABA FUNCTION IN CAENORHABDITIS-ELEGANS NATURE McIntire, S. L., Jorgensen, E., Horvitz, H. R. 1993; 364 (6435): 334-337

    Abstract

    gamma-Aminobutyric acid (GABA) neurotransmission is widespread in vertebrate and invertebrate nervous systems. Here we use a genetic approach to identify molecules specific to GABA function. On the basis of the known in vivo roles of GABAergic neurons in controlling behaviour of the nematode Caenorhabditis elegans, we identified mutants defective in GABA-mediated behaviours. Five genes are necessary either for GABAergic neuronal differentiation or for pre- or postsynaptic GABAergic function. The gene unc-30 is required for the differentiation of a specific type of GABAergic neuron, the type-D inhibitory motor neuron. The gene unc-25 is necessary for GABA expression and probably encodes the GABA biosynthetic enzyme glutamic acid decarboxylase. The genes unc-46 and unc-47 seem to be required for normal GABA release. Finally, the gene unc-49 is apparently necessary postsynaptically for the inhibitory effect of GABA on the body muscles and might encode a protein needed for the function of a GABAA-like receptor. Some of these genes are likely to encode previously unidentified proteins required for GABA function.

    View details for Web of Science ID A1993LN57000056

    View details for PubMedID 8332190

  • GENES NECESSARY FOR DIRECTED AXONAL ELONGATION OR FASCICULATION IN C-ELEGANS NEURON McIntire, S. L., Garriga, G., WHITE, J., Jacobson, D., Horvitz, H. R. 1992; 8 (2): 307-322

    Abstract

    The outgrowth of single axons through different cellular environments requires distinct sets of genes in the nematode C. elegans. Three genes are required for the pioneering circumferential outgrowth of identified motor neuron axons between the lateral hypodermal cell membrane and the basal lamina. Three other genes are required for the longitudinal outgrowth of these axons along preexisting axon bundles as well as for the fasciculation of axons within these neuron bundles. Five additional genes are required for circumferential outgrowth, longitudinal outgrowth, and fasciculation; mutations in three of these genes disrupt axon ultrastructure, suggesting that they function in axon formation rather than in axon guidance.

    View details for Web of Science ID A1992HE93000011

    View details for PubMedID 1739461

  • A GENETIC PATHWAY FOR THE DEVELOPMENT OF THE CAENORHABDITIS-ELEGANS HSN MOTOR NEURONS NATURE Desai, C., Garriga, G., McIntire, S. L., Horvitz, H. R. 1988; 336 (6200): 638-646

    Abstract

    Thirty-five genes define a pathway for the development of the hermaphrodite-specific neurons (HSNs) in Caenorhabditis elegans. Some of these genes affect only one HSN trait, demonstrating that HSN migration, axonal outgrowth and serotonin expression are mutually independent events in HSN development; others, some of which are regulatory, affect multiple HSN traits. Nearly all are pleiotropic, revealing that the genes specifying HSN development also function in the development of other cell types.

    View details for Web of Science ID A1988R363900046

    View details for PubMedID 3200316

  • HYPOTHALAMIC CATECHOLAMINE CHANGES UNDER ACUTE STRESS OCCUR INDEPENDENTLY OF NICOTINIC STIMULATION NEUROSCIENCE LETTERS Roth, K. A., McIntire, S. L., Lorenz, R. G., BARCHAS, J. D. 1982; 28 (1): 47-50

    View details for Web of Science ID A1982NC39700008

    View details for PubMedID 7063143

  • NICOTINIC-CATECHOLAMINERGIC INTERACTIONS IN RAT-BRAIN - EVIDENCE FOR CHOLINERGIC NICOTINIC AND MUSCARINIC INTERACTIONS WITH HYPOTHALAMIC EPINEPHRINE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Roth, K. A., McIntire, S. L., BARCHAS, J. D. 1982; 221 (2): 416-420

    Abstract

    The i.p. injection of nicotine produced several changes in regional catecholamine concentrations in rat brain. These changes were blocked by the centrally active nicotinic antagonist mecamylamine, but not by the quaternary nicotinic antagonist hexamethonium. An examination of the effects of various cholinergic agents on hypothalamic epinephrine concentrations revealed several interesting findings. Central muscarinic antagonism or peripheral muscarinic agonism decreased hypothalamic epinephrine concentrations. The anticholinesterase physostigmine decreased hypothalamic epinephrine concentrations and this effect was blocked by the centrally acting nicotinic antagonist mecamylamine, but not by hexamethonium, scopolamine or methscopolamine. These findings indicate an interaction of cholinergic receptors, both nicotinic and muscarinic, with hypothalamic epinephrine.

    View details for Web of Science ID A1982NQ08000024

    View details for PubMedID 7077536

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