Molecular neuroscience

Professor Isabel Bermudez-Diaz, Dr Andrew Jones, Dr Mike Franklin

The Molecular Neuroscience Group in the Department of Biological and Medical Sciences has a long-term interest in the structural and functional relationships of ligand-gated ion channels, with particular emphasis on human and invertebrate cys -loop ligand-gated ion channels. These ion channels have been implicated in a wide range of diseases of the human brain, including Alzheimer’s and Parkinson’s diseases, Tourette syndrome, schizophremia, autism, drug addiction and attention deficit disorders. In invertebrates, they are targets for successful insecticides such as the neonicotinoids as well as for drugs used to treat parasitic worms.

Mammalian Cys-loop ligand-gated ion channels
The overall goal of Prof Isabel Bermudez’s research is to define the functional architecture of human ion channels. The techniques of molecular biology, in vitro functional studies using primary or clonal cell cultures, radioligand-binding assays, concatenated receptors and electrophysiological recordings are combined to provide a multidisciplinary approach to the topic. We have shown that the function of diverse nAChR subtypes can be influenced by many types of chemical compounds, ranging from cytisine to dihydropyridines and by auto-antibodies. We have shown that the α4β2 nAChR assembles into alternate stoichiometries that differ significantly in pharmacological properties and that stoichiometry-specific subunit interfaces define the functional properties of these receptors.

Invertebrate Cys-loop ligand-gated ion channels
In the laboratory of Dr Andrew Jones, the overall goal of the research is to study the gene diversity of cys-loop ligand-gated ion channels in different invertebrate species and determine the resulting functional and pharmacological properties, using a combination of techniques including genome sequence analysis, molecular biology and electrophysiology.

Psychopharmacology and Neuroendocrinology
Dr Mike Franklin's main interests are in the fields of psychopharmacology and neuroendocrinology. These interests have been further developed through the study of psychotropic drug action in basic (animals) and clinical studies in both healthy people and patients to research the aetiology of psychiatric illness, especially depression and related disorders such as obsessive compulsive disorder and eating disorders.

These research areas have also lead to an interest in therapeutic drug monitoring and metabolism in psychiatry. Other side interests have also been developed such as sexual dimorphism e.g. why do women get eating disorders and men generally do not and why are women more sensitive to many psychotropic drugs than men? He has developed an interest in the use of natural compounds as treatments in psychiatric illness, with special emphasis on St John’s wort, chromium 3+ salts and the amino acids, tryptophan and tyrosine for use in depression and smoking addiction.

Current studies in new animal models of resistant depression and depressed patients emphasise the importance of the renin-angiotensin-aldosterone system as a novel new target area for antidepressant action and also as a possible new biomarker for the onset of depression.

 

Current Projects

Functional architecture of the mammalian α4β2 nAChR
The α4β2 nAChR is the most abundant nAChR in the brain where it forms the high-affinity binding site for nicotine. When expressed in heterologous systems α4 and β2 subunits produce two alternate stoichiometries, (α4)2(β2)3, and (α4)3(β2)2, that differ in functional pharmacology, desensitisation, single channel properties and sensitivity to chronic exposure to nicotine. We are investigating the structural basis for these differences using a variety of approaches including concatenated receptors, functional studies in Xenopus oocytes, SCAM technology and alanine substitutions.

Characterising the functional spectrum of the mosquito GABA receptor
The insect GABA receptor is a known insecticide target. In several insect species, the GABA receptor undergoes RNA A-to-I editing, effectively generating species-specific variants that could not have been detected by looking at the genome sequence. We are using the mosquito GABA receptor to investigate the impact of species-specific RNA editing on receptor functional properties as well as sensitivity to insecticides.

 

Andrew Jones, Alexandra Cuevas, Karina New, Merve Oncul, Constanza Alcaino, Simone Mazzaferro
Jennina Taylor-Wells, Isabel Bermudez, Federica Gasparri

 

People

  • Professor Isabel Bermudez-Diaz - Research Group Leader
  • Dr Andrew Jones – Research Group Leader
  • Dr Mike Franklin - Visiting Researcher
  • Patricio Iturriags Vasquez - Visiting Researcher (Associated Professor, University of Chile)
  • Dr Jennina Taylor-Wells – Post-doctoral researcher
  • Constanza Alcaino Ayala – PhD student
  • Karina New – PhD student
  • Silvia Garcia del Villar – PhD student
  • Simone Mazzaferro – Associate Research Fellow

 

Collaborations

  • Lilly Research Centre, Surrey
  • Department of Chemistry, Faculty of Sciences, University of Chile, Santiago, Chile
  • Division of Neurobiology, Barrow Neurological Institute, Arizona
  • University of Birmingham and NHS Stop Smoking Clinics in Birmingham and Oxford PCTs.
  • University of Oxford Department of Psychiatry (Neurosciences), Oxford

 

Publications

Professor Isabel Bermudez-Diaz

Dr Andrew Jones

Dr Mike Franklin

CONTACT US

Prof Isabel Bermudez-Diaz
ibermudez@brookes.ac.uk
+44 (0) 1865 483292

Dr Andrew Jones
a.jones@brookes.ac.uk
+44 (0) 1865 483602

Dr Mike Franklin
mfranklin@brookes.ac.uk
+44 (0) 1865 483646

Funding

The Wellcome Trust
BBSRC
TCS
The Royal Society
SEPOC
The Leverhulme Trust
CRUK
Oxford Brookes University
Bristol-Myers-Squibb

 

 


Benallegue et al. Br J Pharmacol 2013

 

Agonist occupation of the site at the alpha4(+)/alpha4(-) interface leads to channel gating through a coupling mechanism involving loop C

Mazzaferro et al. J Biol Chem 2011

 


Mazzaferro et al. J Biol Chem 2011

 


Taylor-Wells et al. J Neurochem 2015