Dual modulation of a potassium channel by the m1 muscarinic and beta2-adrenergic receptors.
Neurotransmitter receptors alter membrane excitability and synaptic efficacy by generating intracellular signals that ultimately change the properties of ion channels. Given their critical role in controlling cell membrane potential, potassium channels are frequently the targets of modulatory signals from many different G protein-coupled receptors. However, due to the heterogeneity of potassium channel expression in vivo, it has been difficult to determine the molecular mechanisms governing the regulation of molecularly defined potassium channels. Through expression studies in Xenopus oocytes and mammalian cells, we found that the m1 muscarinic acetylcholine receptor (mAChR) potently suppresses a cloned delayed rectifier potassium channel, termed RAK, through a pathway involving phospholipase C activation and direct tyrosine phosphorylation of the RAK protein. In contrast, we found that RAK channel activity is strongly enhanced following agonist activation of beta2-adrenergic receptors; this effect requires a single PKA consensus phosphorylation site located near the amino terminus of the channel protein. These results demonstrate that a specific type of potassium channel that is widely expressed in the mammalian brain and heart is subject to both positive and negative regulation by G protein-dependent pathways.
Peralta
E G
EG
Dept. of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
D000595:Amino Acid Sequence; D000818:Animals; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D043643:Receptor, Muscarinic M1; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D011976:Receptors, Muscarinic / Q000502:physiology*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism; D014981:Xenopus
D015221:Potassium Channels; D043643:Receptor, Muscarinic M1; D018343:Receptors, Adrenergic, beta-2; D011976:Receptors, Muscarinic; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D010738:Type C Phospholipases