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Cl concentration changes and desensitization of GABAA and glycine receptors
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
2011 (English)In: The Journal of General Physiology, ISSN 0022-1295, Vol. 138, no 6, 609-626 p.Article in journal (Refereed) Published
Abstract [en]

Desensitization of ligand-gated ion channels plays a critical role for the information transfer between neurons. The current view on γ-aminobutyric acid (GABA)A and glycine receptors includes significant rapid components of desensitization as well as cross-desensitization between the two receptor types. Here, we analyze the mechanism of apparent cross-desensitization between native GABAA and glycine receptors in rat central neurons and quantify to what extent the current decay in the presence of ligand is a result of desensitization versus changes in intracellular Cl concentration ([Cl]i). We show that apparent cross-desensitization of currents evoked by GABA and by glycine is caused by changes in [Cl]i. We also show that changes in [Cl]i are critical for the decay of current in the presence of either GABA or glycine, whereas changes in conductance often play a minor role only. Thus, the currents decayed significantly quicker than the conductances, which decayed with time constants of several seconds and in some cells did not decay below the value at peak current during 20-s agonist application. By taking the cytosolic volume into account and numerically computing the membrane currents and expected changes in [Cl]i, we provide a theoretical framework for the observed effects. Modeling diffusional exchange of Cl between cytosol and patch pipettes, we also show that considerable changes in [Cl]i may be expected and cause rapidly decaying current components in conventional whole cell or outside-out patch recordings. The findings imply that a reevaluation of the desensitization properties of GABAA and glycine receptors is needed.

Place, publisher, year, edition, pages
2011. Vol. 138, no 6, 609-626 p.
National Category
Physiology
Identifiers
URN: urn:nbn:se:umu:diva-2614DOI: 10.1085/jgp.201110674OAI: oai:DiVA.org:umu-2614DiVA: diva2:140827
Available from: 2007-10-04 Created: 2007-10-04 Last updated: 2013-10-25Bibliographically approved
In thesis
1. GABA-, glycine- and glutamate-induced currents in rat medial preoptic neurons: functional interactions and modulation by capsaicin
Open this publication in new window or tab >>GABA-, glycine- and glutamate-induced currents in rat medial preoptic neurons: functional interactions and modulation by capsaicin
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The medial preoptic nucleus (MPN) of the hypothalamus plays a major role in many functions involved in maintaining bodily homeostasis, such as thermoregulation and osmoregulation, as well as in the control of complex behaviours, e.g. sexual behaviour. A fundamental basis for the control and execution of these functions is the synaptic communication between neurons of the MPN. However, the functional properties of the synapses involved are largely unknown. The present thesis is a study of ligand-gated ion channels involved in the pre- and post-synaptic aspects of neuronal communication in the MPN of rat. The aim was to clarify synaptic properties in the MPN, to identify the major channel types involved and to obtain a better understanding of their functional properties.

By fast application of agonists to isolated neurons, it was first demonstrated that all neurons responded to glutamate with currents mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and a majority of neurons also with currents mediated by N-Methyl-D-aspartate (NMDA) receptors. All neurons also responded to γ-aminobutyric acid (GABA) and glycine with currents mediated by GABAA receptors and glycine receptors, respectively. These findings show that fast-acting excitatory and inhibitory amino-acid transmitters are most likely important for communication between hypothalamic neurons.

Application of agonists to isolated neurons revealed cross-talk, detected as an apparent cross-desensitization, between the responses to GABA and those to glycine. Parallel analysis of current and conductance, using gramicidin-perforated patches to avoid perturbing intracellular chloride concentration, showed that the cross-talk was not dependent on a direct interaction between the receptors as previously suggested, but was a consequence of the change in the intracellular chloride concentration during receptor activation. Strengthened by a computer model, the analysis also showed that the current decay in the presence of GABA or glycine was mainly due to a change in the chloride driving force and that receptor desensitization played a minor role only.

The role of thermo-sensitive transient receptor potential TRPV1 channels in the regulation of glutamate- and GABA-mediated transmission was studied in the slice preparation, where much of the synaptic connections between neurons are preserved. It was shown that application of the TRPV1 agonist capsaicin increased the frequency of excitatory AMPA receptor- mediated as well as inhibitory GABAA receptor-mediated postsynaptic currents. This effect was partly presynaptic and demonstrates that TRP channels play a role in regulating synaptic transmission in the MPN. The results imply that such mechanisms may possibly contribute to the thermoregulation by MPN neurons.

Place, publisher, year, edition, pages
Umeå: Integrativ medicinsk biologi, 2007. 31 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1122
Keyword
medial preoptic nucleus, synaptic transmission, glutamate, GABA, glycine, TRPV1
National Category
Physiology
Identifiers
urn:nbn:se:umu:diva-1383 (URN)978-91-7264-408-3 (ISBN)
Public defence
2007-10-26, BiA201, Biologihuset, Umeå universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2007-10-04 Created: 2007-10-04 Last updated: 2009-05-26Bibliographically approved

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Druzin, MichaelJohansson, Staffan

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