Transport and recycling of neurotransmitters and amino acids.
The Chaudhry group is focused on the functional mechanisms of transporter proteins involved in the cycling of the neurotransmitters glutamate and GABA in the central nervous system. In particular, we want to investigate the molecular mechanisms involved in the transport of glutamine from astroglial cells and into neurons for neurotransmitter generation, and their subsequent transport into vesicles. We also want to unravel the contribution of glutamine dynamics to the regulation of quantal size, neuronal firing frequencies and synaptic plasticity. Overall, the program will elucidate (patho-) functional roles of amino acid transporters in neuronal signaling as well as identify their potentials as therapeutic targets (relevant background information).
- To unravel the functional mechanisms by which transporter proteins translocate neurotransmitters and amino acids across membranes
- To determine their physiological and pathophysiological roles (e.g., in neurotransmitter recycling, epilepsy, neoplasia, pH regulation, insulin secretion)
- To identify potential therapeutic targets among amino acid transporters
- We have contributed to the characterisation of Slc38, a novel family of plasma membrane amino acid transporters. The Slc38 family includes the System A Transporters (SAT) and System N Transporters (SN), systems that are capable of translocating amino acids, such as glutamine, across the cell membrane.
- We have shown isoform specific characteristics in transport mechanisms and regulation. SN1 (aka Slc38A3), for example, is electroneutral, contains a pH response element, and is targeted by PKCα and PKCγ, whereas SAT1 and SAT2 are electrogenic and generate higher concentration gradients.
- We have demonstrated that the Slc38 proteins have cell-specific expression patterns. For example, SN1 (Slc38A3) is xpressed in astroglia, whereas SAT1 (Slc38A1) and SAT2 (Slc38A2) are enriched in GABAergic and glutamatergic neurons, respectively.
- We have characterized other transporters, including several vesicular transporter proteins.
- We have shown the localization of various transporters by high resolution immunocytochemical techniques, such as immunogold electron microscopy.
- High resolution immuno-cytochemical techniques (e.g., immunogold electron microscopy, confocal laser scanning microscopy)
- Two-electrode voltage clamp electrophysiology (TEVC)
- Ratiometric analyses of ion fluxes
- Hamdani EH, Gudbrandsen M, Bjørkmo M, Chaudhry FA (2012) The system N transporter SN2 doubles as a transmitter precursor furnisher and a potential regulator of NMDA receptors. Glia, 60(11):1671–1683 [Epub 2012 Jul 20.]
- Haeberle J, Shahbeck N, Ibrahim K, Schmitt B, Scheer I, O'Gorman R, Chaudhry FA, Ben-Omran T (2012) Glutamine supplementation in a child with inherited GS deficiency improves the clinical status and partially corrects the peripheral and central amino acid imbalance. Orphanet J Rare Dis, 7(1):48. [Epub 2012 Jul 25.]
- Nissen-Meyer LSH, Popescu MC, Hamdani EH, Chaudhry FA (2011) PKC-mediated phosphorylation of a single serine residue on the rat glial glutamine transporter SN1 governs its membrane trafficking. J Neurosci, 31(17):6565-75.
- Solbu TT, Bjørkmo M, Berghuis P, Harkany T, Chaudhry FA (2010) SAT1, a glutamine transporter, is preferentially expressed in GABAergic neurons. Front Neuroanat, 8;4:1. [Epub 2009 Dec 30.]
- Jenstad M, Quazi AZ, Zilberter M, Haglerød C, Berghuis P, Saddique N, Goiny M, Buntup D, Davanger S, Haug FMS, Barnes CA, McNaughton BL, Ottersen OP, Storm-Mathisen J, Harkany T, Chaudhry FA (2009) System A transporter SAT2 mediates replenishment of dendritic glutamate pools controling retrograde signaling by glutamate. Cereb Cortex, 19:1092-1106. [Epub 2008 Oct 1.]
- Boulland JL, Jenstad M, Boekel AJ, Wouterlood FG, Edwards RH, Storm-Mathisen J, Chaudhry FA (2009) Vesicular glutamate and GABA transporters sort to distinct sets of vesicles in a population of presynaptic terminals. Cereb Cortex, 19(1):241-8. Epub 2008 May 22.
- Solbu TT, Boulland JL, Zahid W, Bredahl MKL, Amiry-Moghaddam M, Storm-Mathisen J, Roberg BA, Chaudhry FA (2005) Induction and targeting of the glutamine transporter SN1 to the basolateral membranes of cortical kidney tubule cells during chronic metabolic acidosis suggest a role in pH regulation. J Am Soc Nephrol, 16(4):869-877. [Epub 2005 Feb 16].
- Fremeau RT, Jr., Kam K, Qureshi T, Johnson J, Copenhagen DR, Storm-Mathisen J, Chaudhry FA, Nicoll RA, Edwards RH (2004) Vesicular glutamate transporters 1 and 2 target to functionally distinct synaptic release sites. Science, 304:1815-1819.
- Chaudhry FA, Schmitz D, Reimer RJ, Larsson P, Gray AT, Nicoll R, Kavanaugh M, Edwards RH (2002) Glutamine uptake by neurons: interaction of protons with system A transporters. J Neurosci, 22:62-72.
- Chaudhry FA, Krizaj D, Larsson P, Reimer RJ, Wreden C, Storm-Mathisen J, Copenhagen D, Kavanaugh MP, Edwards RH (2001) Coupled and uncoupled proton movement by amino acid transport system N. EMBO J, 20:7041-7051.
- Chaudhry FA, Reimer RJ, Krizaj D, Barber D, Storm-Mathisen J, Copenhagen DR, Edwards RH (1999) Molecular analysis of System N suggests novel physiological roles in nitrogen metabolism and synaptic transmission. Cell, 99:769-780.
- Chaudhry FA, Lehre KP, Van Lookeren Campagne M, Ottersen OP, Danbolt NC, Storm-Mathisen J (1995) Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry. Neuron, 15:711-720.
The Chaudhry Group is also associated to the Centre for Molecular Biology and Neuroscience.