Modulation of the heteromeric Kir4.1–Kir5.1 channel by multiple neurotransmitters via Gαq-coupled receptors

✍ Scribed by Asheebo Rojas; Junda Su; Liang Yang; Ming Lee; Ningren Cui; Xiaoli Zhang; Dyanna Fountain; Chun Jiang

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 644 KB
• Volume: 214
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.21169

✦ Synopsis

Abstract

The heteromeric Kir4.1–Kir5.1 channel is a candidate sensing molecule for central CO~2~ chemoreception. Since central CO~2~ chemoreception is subject to neural modulations, we performed studies to test the hypothesis that the Kir4.1–Kir5.1 channel is modulated by the neurotransmitters critical for respiratory control, including serotonin (5‐HT), substance‐P (SP), and thyrotropin releasing hormone (TRH). The heteromeric Kir4.1–Kir5.1 channel was strongly inhibited by SP, TRH, and 5‐HT when expressed in Xenopus oocytes, whereas these neurotransmitters had no effect on the homomeric Kir4.1 channel. Such an inhibition was dose‐dependent and relied on specific G~αq~‐protein‐coupled receptors and protein kinase C (PKC). No direct interaction of the channel with G‐proteins was found. Channel sensitivity to CO~2~/pH was not compromised with the inhibition by these neurotransmitters, as the channel remained to be inhibited by acidic pH following an exposure to the neurotransmitters. The firing rate of CO~2~‐sensitive brainstem neurons cultured in microelectrode arrays was augmented by SP or a 5‐HT2A receptor agonist, which was blocked by PKC inhibitors suggesting that PKC underscores the inhibitory effect of SP and 5‐HT in cultured brainstem neurons as well. Immunostaining showed that both Kir4.1 and Kir5.1 proteins were co‐localized in the cultured brainstem neurons. These results therefore indicate that the heteromeric Kir4.1–Kir5.1 channel is modulated by the neurotransmitters critical for respiratory control, suggesting a novel neuromodulatory mechanism for the chemosensitivity of brainstem neurons to elevated PCO~2~ and acidic pH. J. Cell. Physiol. 214:84–95, 2008. © 2007 Wiley‐Liss, Inc.