Down-regulation of mRNA coding for cGIRK1 in cultured embryonic chicks atrial cells following prolonged exposure to muscarinic agonist

Gadbut, Albert P.; Pan, C.; Wang, G.K.; Fadous, S.; Galper, Jonas B.

doi:10.1016/0024-3205(95)93756-5

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“…This is the first direct demonstration of the down-regulation of a G-protein-coupled effector molecule by receptor activation in ovo. Although a preliminary report in abstract form (21) has reported a transient decrease in GIRK1 mRNA in cultured atrial cells after carbachol treatment, the results here demonstrate large and long lasting decreases in the levels of GIRK1 and GIRK4 mRNA as well as GIRK1 polypeptide levels after persistent mAChR activation in vivo. Interestingly, no decrease is detected in GIRK1 mRNA expression in ventricles after prolonged agonist treatment.…”

Section: Discussionmentioning

confidence: 72%

Tissue-specific Regulation of G-protein-coupled Inwardly Rectifying K+ Channel Expression by Muscarinic Receptor Activation in Ovo

Thomas

Chmelar

et al. 1997

Journal of Biological Chemistry

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We investigated the effects of muscarinic acetylcholine receptor stimulation on the expression levels of the G-protein-coupled inwardly rectifying K ؉ channel (GIRK) subunits using solution hybridization and immunoblot analyses. We report here that treatment of chick embryos in ovo with muscarinic agonist causes decreases in mRNA levels encoding GIRK1 and GIRK4 in atria but does not alter GIRK1 expression in ventricles. In addition, GIRK1 protein levels also demonstrate a decrease in atria upon muscarinic acetylcholine receptor stimulation. Numerous receptors couple to the activation of the GIRK family of inwardly rectifying K ؉ channels; thus, these decreases represent a novel mechanism for regulating physiological responses to chronic agonist exposure. Muscarinic acetylcholine receptors (mAChRs)1 couple to heterotrimeric G-proteins to regulate multiple effector molecules such as the GIRK family of inwardly rectifying K ϩ channels and the enzymes adenylyl cyclase and phospholipase C. Acetylcholine released from parasympathetic neurons binds to mAChRs in the heart, resulting in a negative chronotropic response. There are five subtypes of mAChR, which are the products of different genes; the decrease in heart rate is caused by the activation of m2 subtype of mAChR in mammalian heart and both m2 and m4 subtypes in chick heart (1-3). The negative chronotropic response is due in part to the activation of I KACh , an outward K ϩ current that hyperpolarizes the cell in the sinus node of the atrium. I KACh is activated directly by pertussis toxin-sensitive heterotrimeric G-proteins coupled to m2 and m4 muscarinic receptors without the mediation of second messengers (4). I KACh is due to an assembly of G-protein-coupled inwardly rectifying K ϩ channels comprising two subunits, GIRK1 and GIRK4 (5).The number of mAChRs expressed in cardiac cells can be regulated by the continued presence of agonist. Persistent activation of cardiac mAChRs leads to receptor sequestration (6), reduction in total receptor number (7), and decreased transcription of the mAChR genes (8). Sequestration of mAChRs occurs within seconds to minutes and involves internalization of receptors from the cell surface (9). Prolonged agonist exposure (hours) results in a decrease in mAChR number and recovery requires de novo protein synthesis (10 -12). Another consequence of continued mAChR activation is a decrease in transcription of mAChR genes. In chick heart, both m2 and m4 mAChR mRNA are decreased in a time-and dose-dependent manner (8). This regulation of mAChR mRNA is dependent on both the activation of phospholipase C and the inhibition of adenylyl cyclase (13). These decreases in receptors at the cell surface and in gene expression result in a reduced physiological response to subsequent receptor stimulation.Although many G-protein-coupled receptors exhibit agonistinduced decreases in expression, little information is available on the consequences of receptor stimulation on effector expression. In this study, we determined the effects of mAChR acti...

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Section: Discussionmentioning

confidence: 72%