Presynaptic GABAB receptors linked to kcnk3 regulate hypoxic chemotransmission in the rat carotid body

University of Central Lancashire / University of Liverpool (2002) J Physiol 543P, S003

Communications: Presynaptic GABAB receptors linked to kcnk3 regulate hypoxic chemotransmission in the rat carotid body

Ian M. Fearon, Min Zhang, Cathy Vollmer and Colin A. Nurse

Department of Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4K1, Canada

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The mammalian carotid body is a chemosensory organ that responds to changes in arterial hypoxia, acidosis and hypercapnia by increasing afferent chemosensory discharge in the carotid sinus nerve, which initiates corrective changes in ventilation. This is brought about by stimulus-induced neurotransmitter release from chemoreceptive glomus (type I) cells onto adjacent afferent petrosal nerve endings (Gonzalez et al. 1994). There is evidence that, at least in mouse, GABA is localized in glomus cells and thus may act as a neurotransmitter/modulator in chemosensory signalling (Oomori et al. 1994).

Carotid body glomus cells and petrosal neurons were isolated from 10- to 12-day-old Wistar rats following humane euthanasia, as previously described (Zhong et al. 1997). Using gene-specific primers, mRNA for both the BR1 and BR2 subtypes of the GABAB receptor was found in isolated glomus cells using RT-PCR. Immunohistochemical staining for these receptors using specific antibodies could also be found in these cells in vitro and in situ. In a functional co-culture model of glomus cell clusters and petrosal neurons, we examined the effects of the GABAB receptor blockers 5-aminovaleric acid (5-AVA) and hydroxysaclofen (OHS) on afferent chemoreceptor signalling due to hypoxia. In the presence of either 100 mM 5-AVA (n = 14) or 50 mM OHS (n = 6), the postsynaptic depolarization due to hypoxia (PO2, 5 mmHg) was significantly enhanced (P < 0.05 for either blocker, ANOVA). These effects were abolished by a selective inhibitor of PKA but not PKC. Hypoxia-induced depolarization of cultured glomus cell clusters could also be enhanced by these blockers. Furthermore, during patch-clamp recordings from glomus clusters, the selective GABAB receptor agonist baclofen enhanced whole-cell K+ current, an effect significantly reduced in the presence of either 5 mM Ba2+ or 10 mM anandamide (P < 0.05 for either blocker, Mann-Whitney test).

These data suggest the release of GABA by glomus cells in response to hypoxia, with the neurotransmitter acting pre-synaptically to modulate the release of GABA and other neurotransmitters by PKA-regulated activation of KCNK3, an O2-sensitive K+ channel known to be expressed in these cells (Buckler et al. 2000).

This work was supported by a Wellcome Trust International Prize Travelling Research Fellowship (grant #061542) to I.M.F., and by grants to C.A.N. from CIHR and NSERC.

All procedures accord with current local guidelines.



Where applicable, experiments conform with Society ethical requirements.

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