Modulation of the heteromeric Kir4.1-Kir5.1 channel by multiple neurotransmitters via Galphaq-coupled receptors.
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(alphaq)-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.
Rojas
Asheebo
A
Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, Georgia 30302-4010, USA.
Su
Junda
J
Yang
Liang
L
Lee
Ming
M
Cui
Ningren
N
Zhang
Xiaoli
X
Fountain
Dyanna
D
Jiang
Chun
C
D000818:Animals; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D018076:DNA, Complementary; D004594:Electrophysiology; D004622:Embryo, Mammalian; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D007150:Immunohistochemistry; D008526:Medulla Oblongata / Q000166:cytology; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D008839:Microelectrodes; D008845:Microinjections; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013997:Time Factors; D014982:Xenopus laevis; D000098854:Kcnj10 Channel
D018076:DNA, Complementary; D000098854:Kcnj10 Channel; D018377:Neurotransmitter Agents; D024661:Potassium Channels, Inwardly Rectifying; D043562:Receptors, G-Protein-Coupled