Uncoupling of cardiac muscarinic and β-adrenergic receptors from ion channels by a guanine nucleotide analogue

Breitwieser, Gerda E.; Szabó, Gábor

doi:10.1038/317538a0

Cited by 514 publications

(249 citation statements)

References 9 publications

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“…Our results are consistent with known mechanisms of channel modulation by transmitters that couple to the Go pathway, specifically high-voltage-activated Ca 2+ channel (14,15) and GIRK channels (33,34). In both examples, modulation of channel function is mediated directly by the βγ dimer, with the α subunit playing a supporting role (35)(36)(37).…”

Section: Discussionsupporting

confidence: 76%

G-protein–mediated inhibition of the Trp channel TRPM1 requires the Gβγ dimer

Shen

Rampino

Carroll

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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ON bipolar cells are critical for the function of the ON pathway in the visual system. They express a metabotropic glutamate receptor (mGluR6) that, when activated, couples to the G o class of G protein. The channel that is primarily responsible for the synaptic response has been recently identified as the transient receptor potential cation channel subfamily M member 1 (TRPM1); TRPM1 is negatively coupled to the mGluR6/Go cascade such that activation of the cascade results in closure of the channel. Light indirectly opens TRPM1 by reducing transmitter release from presynaptic photoreceptors, resulting in a decrease in mGluR6 activation. Conversely, in the dark, binding of synaptic glutamate to mGluR6 inhibits TRPM1 current. Closure of TRPM1 by G-protein activation in the dark is a critical step in the process of ON bipolar cell signal transduction, but the precise pathway linking these two events is not understood. To address this question, we measured TRPM1 activity in retinal bipolar cells, in human ependymal melanocytes (HEMs) that endogenously express TRPM1, and in HEK293 cells transfected with TRPM1. Dialysis of the Gβγ subunit dimer, but not Gα o , closed TRPM1 channels in every cell type that we tested. In addition, activation of an endogenous G-protein-coupled receptor pathway in HEK293 cells that releases Gβγ without activating Go protein also closed TRPM1 channels. These results suggest a model in which the Gβγ dimer that is released as a result of the dissociation from Gα o upon activation of mGluR6 closes the TRPM1 channel, perhaps via a direct interaction. patch clamp | calcium imaging R etinal ON bipolar cells are connected to photoreceptors through a sign-inverting synapse. At this synapse, glutamate binds to the metabotropic glutamate receptor mGluR6, which couples to the closure of a cation-selective transduction channel. Insight into the molecular identity of the transduction channel was gained from the observation that low levels of mRNA encoding the transient receptor potential ion channel TRPM1 was associated with a form of congenital stationary night blindness (CSNB) in a population of Appaloosa horses (1). Soon after, it was shown that ON bipolar cell function was absent or severely impaired in a mouse model that lacked TRPM1 expression (2-4), although there is evidence that one or more classes of cone-driven ON bipolar cells may use an additional channel (3). Mutations in TRPM1 have now been positively linked to CSNB in humans as well (5-7). Taken together, studies of mouse, horse, and human provide convincing evidence that the ON bipolar cell transduction channel is composed of TRPM1, either alone or in conjunction with other channels. However, all these studies do not provide insight into the mechanism by which activation of mGluR6 leads to closure of TRPM1.The metabotropic receptor mGluR6 preferentially couples to the G o class of G protein, both in bipolar cells (8, 9) and expression systems (10, 11). Activation of mGluR6 and, correspondingly, Go, results in closure of TRPM1. However...

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Section: Discussionsupporting

confidence: 76%

G-protein–mediated inhibition of the Trp channel TRPM1 requires the Gβγ dimer

Shen

Rampino

Carroll

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Scamps et al ( , 1992 (Fabiato & Fabiato, 1979;Tsien & Rink, 1980). A, et al 1996), which is analogous to the coupling mechanism of the muscarinic ACh receptor or P,-purinoceptor for the activation of the muscarinic K+ channel (Pfaffinger, Martin, Hunter, Nathanson & Hille, 1985;Breitwieser & Szabo, 1985;Kurachi et al 1986). The question then arises as to whether P2-purinoceptors also link with a PTXsensitive inhibitory G protein (Gi) which counteracts the ,-adrenergic stimulation of adenylate cyclase, as suggested for the muscarinic ACh receptor (Hescheler, Kameyama & Trautwein, 1986;Hwang, Horie, Nairn & Gadsby, 1992) and P,-purinoceptor (Isenberg, Cerbai & Kl6ckner, 1987).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of delayed rectifier K+ current by P2‐purinoceptor stimulation in guinea‐pig atrial cells.

Matsuura

Tsuruhara

Sakaguchi

et al. 1996

The Journal of Physiology

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1. We studied the effects of P2-purinoceptor stimulation on the delayed rectifier K+ current (IK) 3. External ADP also enhanced IK in a dose-dependent manner with a K% of 3-65 /UM, whereas adenosine (100 /,M) failed to evoke this response. Theophylline (500 ,tM), a blocker of the P1-purinoceptor, did not antagonize the stimulating action of ATP on IK. These results indicate that IK was enhanced via P2-purinoceptors. 4. External ATP or ADP did not produce a significant change in the current kinetics of IK.

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“…(1) The response to ACh requires the presence of GTP [24][25][26] . (2) Non-hydrolysable analogs of GTP (GTP-γ-S and Gpp(NH)p) produce irreversible increases in K + channel activity 27 that are independent of agonist binding 24,25,28 (3) PTX blocks the actions of ACh [24][25][26]28 .…”

Section: G Proteins As Regulators Of K + Channelsmentioning

confidence: 99%

G proteins as regulators of ion channel function

Dunlap

Holz

Rane

1987

Trends in Neurosciences

172

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Virtually unknown just a decade ago, GTP-binding proteins (G proteins) have become a major focus of current research. This family of closely related proteins transduce extracellular signals (such as hormones, neurotransmitters and sensory stimuli) into effector responses 1,2 . It is now evident that ion channel permeability is one such effector response. In fact, the striking increase in the frequency of reports that demonstrate G protein-regulated ion channel function suggests that channels whose permeability mechanism can be altered by a G protein-mediated process may be more the rule than the exception. It is well-known that the cAMP-dependent modulation of ion channels is under the control of G proteins that regulate adenylate cyclase activity 3,4 . However recent studies demonstrate that G proteins also transduce agonist-induced changes in channel activity that do not involve adenylate cyclase. It is on this aspect of G protein signal transduction that this review will focus.Much of our information on the mechanisms underlying G protein function comes from research on G s , the regulatory protein mediating hormonal stimulation of adenylate cyclase. According to one presently accepted model (for review see Ref. 5), G s , in the non-activated state, exists as a heterotrimer of α-, β-and γ-subunits with GDP bound on the α-subunit (G-GDP). The interaction of agonist, receptor, and G-GDP accelerates the exchange of GTP for bound GDP. Binding of GTP by the α-subunit stimulates both the dissociation of G-GTP from the agonist-receptor complex, and the dissociation of the G protein itself into α-GTP (the active subunit with GTPase activity) and βγ (the regulatory dimer). Via a mechanism that remains to be identified, α-GTP promotes an increase in adenylate cyclase activity. The action of α-GTP is terminated through the α-subunit-mediated hydrolysis of GTP followed by reassociation of the α-subunit with free βγ to reform the inactive G-GDP. The agonistinduced activation of a G protein and its deactivation through hydrolysis of GTP is illustrated schematically by the cycle in Fig. 1. This general scheme of events has been postulated to underlie the mechanism of action of other, more recently discovered G proteins (G i and G o ) 6-8 , although the receptors and, in some cases, the effector enzymes involved are different. In addition to its inhibitory role in the regulation of adenylate cyclase, a G i -like protein may, for example, control the activity of other second messenger-generating enzymes such as phospholipase C or phospholipase A 2 9-12 . Similarly, it has been thought that G o , a regulatory protein found in abundance in neural tissue (~1% of total protein), might also be linked to enzyme effectors other than adenylate cyclase but, until recently, the α-subunit of G o has had no demonstrable physiological function. A recent paper by Hescheler et al. 13 indicates that α o may play a pivotal role in regulating Ca 2+ channel function in neurons. Furthermore, the recently reported co-localization of α o i...

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Uncoupling of cardiac muscarinic and β-adrenergic receptors from ion channels by a guanine nucleotide analogue

Cited by 514 publications

References 9 publications

G-protein–mediated inhibition of the Trp channel TRPM1 requires the Gβγ dimer

G-protein–mediated inhibition of the Trp channel TRPM1 requires the Gβγ dimer

Enhancement of delayed rectifier K+ current by P2‐purinoceptor stimulation in guinea‐pig atrial cells.

G proteins as regulators of ion channel function

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