Medical Sciences Commons^™

Differential Expression Of Toll-Like Receptors 2 And 4 In Tissues Of The Human Female Reproductive Tract, Patricia A. Pioli, Eyal Amiel, Todd M. Schaefer, John E. Connolly, Charles R. Wira, Paul M. Guyre

Dartmouth Scholarship

Toll-like receptor (TLR) signal transduction is a central component of the innate immune response to pathogenic challenge. Although recent studies have begun to elucidate differences in acquired immunity in tissues of the human female reproductive tract, there is a relative paucity of work regarding innate defense mechanisms. We investigated TLR mRNA and protein expression in tissues of the human female reproductive tract. Constitutive mRNA expression of TLRs 1 to 6 was observed in fallopian tubes, uterine endometrium, cervix, and ectocervix. Furthermore, transcripts of the signaling adapter MyD88 and the accessory molecule CD14 were also detected in all tissues assayed. Quantitative …

Multiple Mechanisms Regulate Numa Dynamics At Spindle Poles, Olga Kisurina-Evgenieva, Gary Mack, Quansheng Du, Ian Macara, Alexey Khodjakov, Duane A. Compton

Dartmouth Scholarship

The large coiled-coil protein NuMA plays an essential role in organizing microtubule minus ends at spindle poles in vertebrate cells. Here, we use both in vivo and in vitro methods to examine NuMA dynamics at mitotic spindle poles. Using fluorescence recovery after photobleaching, we show that an exogenously expressed green-fluorescent-protein/NuMA fusion undergoes continuous exchange between soluble and spindle-associated pools in living cells. These dynamics require cellular energy and display an average half-time for fluorescence recovery of approximately 3 minutes. To explore how NuMA dynamics at spindle poles is regulated, we exploited the association of NuMA with microtubule asters formed in …

Binding Between The Niemann–Pick C1 Protein And A Photoactivatable Cholesterol Analog Requires A Functional Sterol-Sensing Domain, Nobutaka Ohgami, Dennis C. Ko, Matthew Thomas, Matthew P. Scott, Catherine C. Y. Chang, Ta-Yuan Chang

Dartmouth Scholarship

Niemann-Pick type C (NPC) 1 protein plays important roles in moving cholesterol and other lipids out of late endosomes by means of vesicular trafficking, but it is not known whether NPC1 directly interacts with cholesterol. We performed photoaffinity labeling of intact cells expressing fluorescent protein (FP)-tagged NPC1 by using [(3)H]7,7-azocholestanol ([(3)H]AC). After immunoprecipitation, (3)H-labeled NPC1-GFP appeared as a single band. Including excess unlabeled sterol to the labeling reaction significantly diminished the labeling. Altering the NPC1 sterol-sensing domain (SSD) with loss-of-function mutations (P692S and Y635C) severely reduced the extent of labeling. To further demonstrate the specificity of labeling, we show that …

Transcriptional Activation Of The Human Prostatic Acid Phosphatase Gene By Nf-Kappab Via A Novel Hexanucleotide-Binding Site., Stanislav Zelivianski, Richard Glowacki, Ming-Fong Lin

Journal Articles: Biochemistry & Molecular Biology

Human prostatic acid phosphatase (PAcP) is a prostate epithelium-specific differentiation antigen. Cellular PAcP functions as a neutral protein tyrosine phosphatase and is involved in regulating androgen-promoted prostate cancer cell proliferation. Despite the fact that the promoter of the PAcP gene has been cloned, the transcriptional factors that regulate PAcP expression remain unidentified. This article describes our analyses of the promoter of the PAcP gene. Deletion analyses of the promoter sequence up to -4893 (-4893/+87) revealed that a 577 bp fragment (-1356/-779) represents the unique positive cis-active element in human prostate cancer cells but not in HeLa cervix carcinoma cells. Interestingly, …

The Tumor Suppressor Lkb1 Kinase Directly Activates Amp-Activated Kinase And Regulates Apoptosis In Response To Energy Stress, Reuben J. Shaw, Monica Kosmatka, Nabeel Bardeesy, Rebecca L. Hurley, Lee A. Witters, Ronald A. Depinho, Lewis C. Cantley

Dartmouth Scholarship

AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status found in all eukaryotic cells. AMPK is activated by stimuli that increase the cellular AMP/ATP ratio. Essential to activation of AMPK is its phosphorylation at Thr-172 by an upstream kinase, AMPKK, whose identity in mammalian cells has remained elusive. Here we present biochemical and genetic evidence indicating that the LKB1 serine/threonine kinase, the gene inactivated in the Peutz-Jeghers familial cancer syndrome, is the dominant regulator of AMPK activation in several mammalian cell types. We show that LKB1 directly phosphorylates Thr-172 of AMPKalpha in vitro and activates its …

Indinavir And Rifabutin Drug Interactions In Healthy Volunteers., Walter K. Kraft, Jacqueline B. Mccrea, Gregory A. Winchell, Alexandra Carides, Richard C. Lowry, Eric J. Woolf, Sandra E. Kusma, Paul J. Deutsch, Howard E Greenberg, Scott A. Waldman

Department of Medicine Faculty Papers

Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healthy subjects. Rifabutin, which induces the expression of cytochrome P450 (CYP) 3A, and indinavir, which inhibits that enzyme system, are frequently coadministered in patients infected with HIV. The second study was undertaken to determine if altering the dose of rifabutin coadministered with indinavir would minimize the drug interaction observed in the first study. Two studies, each with a three-period crossover design, were performed. In study 1, standard doses of rifabutin and indinavir (300 mg of rifabutin qd and 800 mg indinavir q8h) were administered as monotherapy (with placebo …

Muc4 Mucin Expression In Human Pancreatic Tumours Is Affected By Organ Environment: The Possible Role Of Tgfbeta2., A. Choudhury, N. Moniaux, A. B. Ulrich, B. M. Schmied, J. Standop, Parviz M. Pour, S. J. Gendler, Michael A. Hollingsworth, J-P Aubert, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

MUC4 is highly expressed in human pancreatic tumours and pancreatic tumour cell lines, but is minimally or not expressed in normal pancreas or chronic pancreatitis. Here, we investigated the aberrant regulation of MUC4 expression in vivo using clonal human pancreatic tumour cells (CD18/HPAF) grown either orthotopically in the pancreas (OT) or ectopically in subcutaneous tissue (SC) in the nude mice. Histological examination of the OT and SC tumours showed moderately differentiated and anaplastic morphology, respectively. The OT tumour cells showed metastases to distant lymph nodes and faster tumour growth (P

Somatotopic Representation Of Action Words In Human Motor And Premotor Cortex, Olaf Hauk, Ingrid Johnsrude, Friedemann Pulvermüller

Brain and Mind Institute Researchers' Publications

Since the early days of research into language and the brain, word meaning was assumed to be processed in specific brain regions, which most modern neuroscientists localize to the left temporal lobe. Here we use event-related fMRI to show that action words referring to face, arm, or leg actions (e.g., to lick, pick, or kick), when presented in a passive reading task, differentially activated areas along the motor strip that either were directly adjacent to or overlapped with areas activated by actual movement of the tongue, fingers, or feet. These results demonstrate that the referential meaning of action words has …

Creation Of Non-Human Primate Neurogenetic Disease Models By Gene Targeting And Nuclear Transfer, Robert B. Norgren

Journal Articles: Genetics, Cell Biology & Anatomy

Genetically modified rhesus macaques are necessary because mouse models are not suitable for a number of important neurogenetic disorders; for example, Kallmann's syndrome, Lesch-Nyhan's disease and Ataxia-Telangiectasia. Mouse models may not be suitable because there may be no mouse ortholog of the human gene of interest, as is the case for Kallmann's syndrome, or because mutant mice do not exhibit the same phenotype observed in humans, as is the the case for Lesch-Nyhan's disease and Ataxia-Telangiectasia. Non-human primate models of neurogenetic diseases are expected to more closely resemble human diseases than existing mouse models. Genetically modified rhesus macaques can be …

The Pharmacokinetics Of Nebulized Nanocrystal Budesonide Suspension In Healthy Volunteers., Walter Kraft, Barry Steiger, Don Beussink, John N. Quiring, Nancy Fitzgerald, Howard E. Greenberg, Scott A. Waldman

Department of Medicine Faculty Papers

Nanocrystal budesonide (nanobudesonide) is a suspension for nebulization in patients with steroid-responsive pulmonary diseases such as asthma. The pharmacokinetics and safety of the product were compared to those of Pulmicort Respules. Sixteen healthy volunteers were administered nanobudesonide 0.5 and 1.0 mg, Pulmicort Respules 0.5 mg, and placebo in a four-way, randomized crossover design. All nebulized formulations were well tolerated, with no evidence of bronchospasm. Nebulization times were significantly shorter for nanobudesonide compared to Pulmicort Respules. Because of a low oral bioavailability, plasma concentration of budesonide is a good marker of lung-delivered dose. The pharmacokinetics of nanobudesonide 0.5 and 1.0 mg …

Interpreting Hemoglobin And Water Concentration, Oxygen Saturation, And Scattering Measured In Vivo By Near-Infrared Breast Tomography, Subhadra Srinivasan, Brian W. Pogue, Shudong Jiang, Hamid Dehghani, Christine Kogel, Sandra Soho, Jennifer J. Gibson, Tor D. Tosteson, Steven P. Poplack, Keith D. Paulsen

Dartmouth Scholarship

Near-infrared spectroscopic tomography was used to measure the properties of 24 mammographically normal breasts to quantify whole-breast absorption and scattering spectra and to evaluate which tissue composition characteristics can be determined from these spectra. The absorption spectrum of breast tissue allows quantification of (i) total hemoglobin concentration, (ii) hemoglobin oxygen saturation, and (iii) water concentration, whereas the scattering spectrum provides information about the size and number density of cellular components and structural matrix elements. These property data were tested for correlation to demographic information, including subject age, body mass index, breast size, and radiographic …

Genetic Polymorphisms Of The Interleukin-1 Gene And Early Marginal Bone Loss Around Endosseous Dental Implants, Hitomi Shimpuku, Yasuhiro Nosaka, Tatsuya Kawamura, Yoichi Tachi, Mitsuko Shinohara, Kiyoshi Ohura

Faculty, Staff and Student Publications

Dental implant surgery commonly proceeds in two stages. It is generally accepted that bone loss around implants does not occur at stage-II surgery because implants do not receive mechanical loading. However, early marginal bone loss around implants occasionally does occur during the healing period. Genetic polymorphisms in the interleukin-1 (IL-1) gene have been reported to be important for bone homeostasis and susceptibility to bone disease. We therefore investigated whether the idiopathic early marginal bone loss around implants is related to polymorphisms in the IL-1 gene. We performed a case-control study. Patients demonstrating marginal bone loss around implants at stage-II surgery …

Gaze-Centered Updating Of Visual Space In Human Parietal Cortex., W Pieter Medendorp, Herbert C Goltz, Tutis Vilis, J Douglas Crawford

Brain and Mind Institute Researchers' Publications

Single-unit recordings have identified a region in the posterior parietal cortex (PPC) of the monkey that represents and updates visual space in a gaze-centered frame. Here, using event-related functional magnetic resonance imaging, we identified an analogous bilateral region in the human PPC that shows contralateral topography for memory-guided eye movements and arm movements. Furthermore, when eye movements reversed the remembered horizontal target location relative to the gaze fixation point, this PPC region exchanged activity across the two cortical lobules. This shows that the human PPC dynamically updates the spatial goals for action in a gaze-centered frame.

Use Of In Vivo-Induced Antigen Technology (Iviat) To Identify Genes Uniquely Expressed During Human Infection With Vibrio Cholerae, Long Hang, Manohar John, Muhammad Asaduzzaman, Emily A. Bridges, Cecily Vanderspurt, Thomas J. Kirn, Ronald K. Taylor

Dartmouth Scholarship

In vivo-induced antigen technology is a method to identify proteins expressed by pathogenic bacteria during human infection. Sera from 10 patients convalescing from cholera infection in Bangladesh were pooled, adsorbed against in vitro-grown El Tor Vibrio cholerae O1, and used to probe a genomic expression library in Escherichia coli constructed from El Tor V. cholerae O1 strain N16961. We identified 38 positive clones in the screen, encoding pili (PilA and TcpA), cell membrane proteins (PilQ, MshO, MshP, and CapK), methyl-accepting chemotaxis proteins, chemotaxis and motility proteins (CheA and CheR), a quorum-sensing protein (LuxP), and four hypothetical proteins. Analysis of immune …

The Lateral Occipital Complex Subserves The Perceptual Persistence Of Motion-Defined Groupings., Susanne Ferber, G Keith Humphrey, Tutis Vilis

Brain and Mind Institute Researchers' Publications

How are the bits and pieces of retinal information assembled and integrated to form the coherent objects that we see? One long-established principle is that elements that move as a group are linked together. For instance a fragmented line-drawing of an object, placed on a background of randomly distributed short lines, can be impossible to see. But if the object moves relative to the background, its shape is instantly recognized. Even after the motion stops, the percept of the object persists briefly before it fades into the background of random lines. Where in the brain does the percept of the …

Crystal Structure Of The Sars Protein From Staphylococcus Aureus, Ronggui Li, Adhar C. Manna, Shaodong Dai, Ambrose L. Cheung, Gongyi Zhang

Dartmouth Scholarship

The expression of virulence determinants in Staphylococcus aureus is controlled by global regulatory loci (e.g., sarA and agr). One of these determinants, protein A (spa), is activated by sarS, which encodes a 250-residue DNA-binding protein. Genetic analysis indicated that the agr locus likely mediates spa repression by suppressing the transcription of sarS. Contrary to SarA and SarR, which require homodimer formation for proper function, SarS is unusual within the SarA protein family in that it contains two homologous halves, with each half sharing sequence similarity to SarA and SarR. Here we report the 2.2 Å …

A Functional Relationship Between Numa And Kid Is Involved In Both Spindle Organization And Chromosome Alignment In Vertebrate Cells, Aime A. Levesque, Louisa Howard, Michael B. Gordon, Duane A. Compton

Dartmouth Scholarship

We examined spindle morphology and chromosome alignment in vertebrate cells after simultaneous perturbation of the chromokinesin Kid and either NuMA, CENP-E, or HSET. Spindle morphology and chromosome alignment after simultaneous perturbation of Kid and either HSET or CENP-E were no different from when either HSET or CENP-E was perturbed alone. However, short bipolar spindles with organized poles formed after perturbation of both Kid and NuMA in stark contrast to splayed spindle poles observed after perturbation of NuMA alone. Spindles were disorganized if Kid, NuMA, and HSET were perturbed, indicating that HSET is sufficient for spindle organization in the absence of …

Probucol Prevents Early Coronary Heart Disease And Death In The High-Density Lipoprotein Receptor Sr-Bi/Apolipoprotein E Double Knockout Mouse, Anne Braun, Songwen Zhang, Helena E. Miettinen, Shamsah Ebrahim, Teresa M. Holm, Eliza Vasile, Mark J. Post

Dartmouth Scholarship

Mice with homozygous null mutations in the high-density lipoprotein receptor SR-BI (scavenger receptor class B, type I) and apolipoprotein E genes fed a low-fat diet exhibit a constellation of pathologies shared with human atherosclerotic coronary heart disease (CHD): hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarctions, cardiac dysfunction (heart enlargement, reduced systolic function and ejection fraction, and ECG abnormalities), and premature death (mean age 6 weeks). They also exhibit a block in RBC maturation and abnormally high plasma unesterified-to-total cholesterol ratio (0.8) with associated abnormal lipoprotein morphology (lamellar/vesicular and stacked discoidal particles reminiscent of those in lecithin/cholesterol acyltransferase deficiency and cholestasis). Treatment …

Residency Program At Michael E Debakey Department Of Surgery, Baylor College Of Medicine, F Charles Brunicardi

Faculty, Staff and Students Publications

No abstract provided.

Copper Chelation Represses The Vascular Response To Injury, Lazar Mandinov, Anna Mandinova, Stanimir Kyurkchiev, Dobroslav Kyurkchiev, Ivan Kehayov, Vihren Kolev, Raffaella Soldi, Cinzia Bagala, Ebo D. De Muinck, Volkhard Lindner, Mark J. Post, Michael Simons

Dartmouth Scholarship

The induction of an acute inflammatory response followed by the release of polypeptide cytokines and growth factors from peripheral blood monocytes has been implicated in mediating the response to vascular injury. Because the Cu2+-binding proteins IL-1alpha and fibroblast growth factor 1 are exported into the extracellular compartment in a stress-dependent manner by using intracellular Cu2+ to facilitate the formation of S100A13 heterotetrameric complexes and these signal peptideless polypeptides have been implicated as regulators of vascular injury in vivo, we examined the ability of Cu2+ chelation to repress neointimal thickening in response to injury. We observed that the oral administration of …

Effects Of Ethanol On Anti-Saccade Task Performance., Sarah A Khan, Kristen Ford, Brian Timney, Stefan Everling

Brain and Mind Institute Researchers' Publications

It has been shown that saccade-related neurons in the superior colliculus (SC) display an increased level of prestimulus activity and a higher stimulus-related burst in action potentials preceding direction errors in the anti-saccade task compared with correct anti-saccades. From this, it has been hypothesized that errors occur when the incoming visual signal in the SC passes a threshold and triggers a reflexive saccade. This hypothesis predicts that an attenuated visual signal will reduce the number of direction errors. Since ethanol has been shown to have a suppressive effect on cortical visual event-related potentials (ERPs), the purpose of the present study …

Hierarchical Processing In Spoken Language Comprehension., Matthew H Davis, Ingrid Johnsrude

Brain and Mind Institute Researchers' Publications

Understanding spoken language requires a complex series of processing stages to translate speech sounds into meaning. In this study, we use functional magnetic resonance imaging to explore the brain regions that are involved in spoken language comprehension, fractionating this system into sound-based and more abstract higher-level processes. We distorted English sentences in three acoustically different ways, applying each distortion to varying degrees to produce a range of intelligibility (quantified as the number of words that could be reported) and collected whole-brain echo-planar imaging data from 12 listeners using sparse imaging. The blood oxygenation level-dependent signal correlated with intelligibility along the …

Mammalian Erv46 Localizes To The Endoplasmic Reticulum–Golgi Intermediate Compartment And To Cis-Golgi Cisternae, Lelio Orci, Mariella Ravazzola, Gary J. Mack, Charles Barlowe, Stefan Otte

Dartmouth Scholarship

Yeast endoplasmic reticulum (ER) vesicle protein Erv46p is a novel membrane protein involved in transport through the early secretory pathway. Investigation of mammalian Erv46 (mErv46) reveals that it is broadly expressed in tissues and protein-secreting cells. By immunofluorescence microscopy, mErv46 displays a crescent-shaped perinuclear staining pattern that is characteristic of the Golgi complex. Quantitative immunoelectron microscopy indicates that mErv46 is restricted to the cis face of the Golgi apparatus and to vesicular tubular structures between the transitional ER and cis-Golgi. Minor amounts of mErv46 reside in ER membranes and later Golgi cisternae. On Brefeldin A treatment, mErv46 redistributes to punctate …

Cell-Cycle Regulatory Proteins In Podocyte Cell In Idiopathic Nephrotic Syndrome Of Childhood., Tarak Srivastava, Robert E. Garola, J M. Whiting, Uri S. Alon

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: The podocyte cell is believed to play an important role in idiopathic nephrotic syndrome (INS) of childhood. In adults with cellular and collapsing focal segmental glomerulosclerosis (FSGS), the expression of cell-cycle regulatory proteins such as p27, p57, and cyclin D is decreased and expression of cyclin A, Ki-67, and p21 is observed in podocyte cells suggestive of a dysregulated podocyte phenotype. We investigated for alterations in the expression of cyclin kinase inhibitors, p27, p57, p21, and cyclins D and A in the podocyte cell of children with INS.

METHODS: Forty-two kidney biopsies were investigated; 14 with minimal-change disease (MCD), …

Human Acyl-Coenzyme A:Cholesterol Acyltransferase Expressed In Chinese Hamster Ovary Cells: Membrane Topology And Active Site Location, Song Lin, Xiaohui Lu, Catherine C.Y. Chang, Ta-Yuan Chang

Dartmouth Scholarship

Acyl-CoA:cholesterol acyltransferase (ACAT) is a membrane-bound enzyme that produces cholesteryl esters intracellularly. Two ACAT genes (ACAT1 and ACAT2) have been identified. The expression of ACAT1 is ubiquitous, whereas that of ACAT2 is tissue restricted. Previous research indicates that ACAT1 may contain seven transmembrane domains (TMDs). To study ACAT2 topology, we inserted two different antigenic tags (hemagglutinin, monoclonal antibody Mab1) at various hydrophilic regions flanking each of its predicted TMDs, and expressed the recombinant proteins in mutant Chinese hamster ovary cells lacking endogenous ACAT. Each tagged ACAT2 was expressed in the endoplasmic reticulum as a single undegraded protein band …

Transfection Of Il-10 Expression Vectors Into Endothelial Cultures Attenuates Alpha4beta7-Dependent Lymphocyte Adhesion Mediated By Madcam-1., Makoto Sasaki, Paul Jordan, Jeff Houghton, Xianmin Meng, Makoto Itoh, Takashi Joh, J Steven Alexander

Department of Dermatology and Cutaneous Biology Faculty Papers

BACKGROUND: Enhanced expression of MAdCAM-1 (mucosal addressin cell adhesion molecule-1) is associated with the onset and progression of inflammatory bowel disease. The clinical significance of elevated MAdCAM-1 expression is supported by studies showing that immunoneutralization of MAdCAM-1, or its ligands reduce inflammation and mucosal damage in models of colitis. Interleukin-10 (IL-10) is an endogenous anti-inflammatory and immunomodulatory cytokine that has been shown to prevent inflammation and injury in several animal studies, however clinical IL-10 treatment remains insufficient because of difficulties in the route of IL-10 administration and its biological half-life. Here, we examined the ability of introducing an IL-10 expression …

Promoters Of The Murine Embryonic Β-Like Globin Genes Ey And Βh1 Do Not Compete For Interaction With The Β-Globin Locus Control Region, Xiao Hu, Michael Bulger, Julia N. Roach, Susan K. Eszterhas, Emmanuel Olivier, Eric Bouhassira, Mark Groudine, Steven Fiering

Dartmouth Scholarship

Mammalian β-globin loci contain multiple β-like genes that are expressed at different times during development. The murine β-globin locus contains two genes expressed during the embryo stage, Ey and βh1, and two genes expressed at both the fetal and postnatal stages, β-major and β-minor. Studies of transgenic human β-like globin loci in mice have suggested that expression of one gene at the locus will suppress expression of other genes at the locus. To test this hypothesis we produced mouse lines with deletions of either the Ey or βh1 promoter in the endogenous murine β-globin locus. Promoter deletion eliminated expression of …

Relationships Between Human Auditory Cortical Structure And Function, Deborah A Hall, Heledd C Hart, Ingrid Johnsrude

Brain and Mind Institute Researchers' Publications

The human auditory cortex comprises multiple areas, largely distributed across the supratemporal plane, but the precise number and configuration of auditory areas and their functional significance have not yet been clearly established. In this paper, we discuss recent research concerning architectonic and functional organisation within the human auditory cortex, as well as architectonic and neurophysiological studies in non-human species, which can provide a broad conceptual framework for interpreting functional specialisation in humans. We review the pattern in human auditory cortex of the functional responses to various acoustic cues, such as frequency, pitch, sound level, temporal variation, motion and spatial location, …

Nucleotide Excision Repair- And Polymerase Eta-Mediated Error-Prone Removal Of Mitomycin C Interstrand Cross-Links, H. Zheng, X. Wang, A. J. Warren, R. J. Legerski, Rodney S. Nairn, Joshua W. Hamilton, Lei Li

Dartmouth Scholarship

Interstrand cross-links (ICLs) make up a unique class of DNA lesions in which both strands of the double helix are covalently joined, precluding strand opening during replication and transcription. The repair of DNA ICLs has become a focus of study since ICLs are recognized as the main cytotoxic lesion inflicted by an array of alkylating compounds used in cancer treatment. As is the case for double-strand breaks, a damage-free homologous copy is essential for the removal of ICLs in an error-free manner. However, recombination-independent mechanisms may exist to remove ICLs in an error-prone fashion. We have developed an in vivo …

Signaling And Regulation Of G Protein-Coupled Receptors In Airway Smooth Muscle., Charlotte K Billington, Raymond B Penn

Department of Medicine Faculty Papers

Signaling through G protein-coupled receptors (GPCRs) mediates numerous airway smooth muscle (ASM) functions including contraction, growth, and "synthetic" functions that orchestrate airway inflammation and promote remodeling of airway architecture. In this review we provide a comprehensive overview of the GPCRs that have been identified in ASM cells, and discuss the extent to which signaling via these GPCRs has been characterized and linked to distinct ASM functions. In addition, we examine the role of GPCR signaling and its regulation in asthma and asthma treatment, and suggest an integrative model whereby an imbalance of GPCR-derived signals in ASM cells contributes to the …