Coordination of Membrane Excitability through a GIRK1 Signaling Complex in the Atria

Nikolov, Emil N.; Ivanova-Nikolova, Tatyana T.

doi:10.1074/jbc.m312861200

Cited by 54 publications

(53 citation statements)

References 43 publications

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“…One possible reason for this deviation from the theoretical curve could be a Gbg-dependent desensitization of GIRK channels. Consistent with this possibility is our recent finding that the native K ACh channels form large signaling complexes with several regulatory proteins in the atrial membrane (Nikolov and Ivanova-Nikolova, 2004). Two of the proteins found in these complexes, RACK1 (receptor for activated C kinase) and bARK (b-adrenergic receptor kinase) can function as Gbg scavengers and, thus, might contribute to GIRK channel desensitization.…”

Section: Gating Mechanism Of Scgirk Channelssupporting

confidence: 59%

Functional Characterization of a Small Conductance GIRK Channel in Rat Atrial Cells

Nikolov

2004

Biophysical Journal

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Muscarinic K 1 (K ACh ) channels are key determinants of the inhibitory synaptic transmission in the heart. These channels are heterotetramers consisting of two homologous subunits, G-protein-gated inwardly rectifying K 1 (GIRK)1 and GIRK4, and have unitary conductance of ;35 pS with symmetrical 150 mM KCl solutions. Activation of atrial K ACh channels, however, is often accompanied by the appearance of openings with a lower conductance, suggesting a functional heterogeneity of G-protein-sensitive ion channels in the heart. Here we report the characterization of a small conductance GIRK (scGIRK) channel present in rat atria. This channel is directly activated by Gbg subunits and has a unitary conductance of 16 pS. The scGIRK and K ACh channels display similar affinities for Gbg binding and are frequently found in the same membrane patches. Furthermore, Gbg-activated scGIRK channels-like their K ACh counterparts-exhibit complex gating behavior, fluctuating among four functional modes conferred by the apparent binding of a different number of Gbg subunits to the channel. The electrogenic efficacy of the scGIRK channels, however, is negligible compared to that of K ACh channels. Thus, Gbg subunits employ the same signaling strategy to regulate two ion channels that are apparently endowed with very different functions in the atrial membrane.

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Section: Gating Mechanism Of Scgirk Channelssupporting

confidence: 59%

Functional Characterization of a Small Conductance GIRK Channel in Rat Atrial Cells

Nikolov

2004

Biophysical Journal

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“…It is probable that the complex is a dynamic one and that the interactions within it are reversible, as indicated by the ability of exogenously expressed G␣ such as G␣ s and G␣ z to replace the endogenous G␣ i/o (32,55) and by the finite affinities of protein-protein interactions in vitro. On the other hand, there are indications that the complex may be rather stable: the components are co-precipitated by a single antibody (40); pull-down experiments show strong binding between GIRK and G␣, G␤␥, and ␤ARK (see Refs. 21, 27, and 41 and Fig.…”

Section: Most Of the Basal Activity Of Girk Is G␤␥-dependent At Allmentioning

confidence: 99%

“…Another possibility is that the scavenger interacts with the effector (GIRK in our case) and is itself sequestered by high doses of the channel, so that the efficiency of G␤␥ sequestration is reduced. Indeed, GIRK and ␤ARK co-immunoprecipitate, along with a number of other components of a multiprotein signaling complex, from atrial cells (40).…”

Section: M-c␤ark Reduces I Basal But It Also Binds To the C Terminumentioning

confidence: 99%

Gβγ-dependent and Gβγ-independent Basal Activity of G Protein-activated K+ Channels

Rishal

Porozov

Yakubovich

et al. 2005

Journal of Biological Chemistry

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Cardiac and neuronal G protein-activated K؉ channels (GIRK; Kir3) open following the binding of G␤␥ subunits, released from G i/o proteins activated by neurotransmitters. GIRKs also possess basal activity contributing to the resting potential in neurons. It appears to depend largely on free G␤␥, but a G␤␥-independent component has also been envisaged. We investigated G␤␥ dependence of the basal GIRK activity (A GIRK,basal ) quantitatively, by titrated expression of G␤␥ scavengers, in Xenopus oocytes expressing GIRK1/2 channels and muscarinic m2 receptors. The widely used G␤␥ scavenger, myristoylated C terminus of ␤-adrenergic kinase (m-c␤ARK), reduced A GIRK,basal by 70 -80% and eliminated the acetylcholine-evoked current (I ACh ). However, we found that m-c␤ARK directly binds to GIRK, complicating the interpretation of physiological data. Among several newly constructed G␤␥ scavengers, phosducin with an added myristoylation signal (m-phosducin) was most efficient in reducing GIRK currents. m-phosducin relocated to the membrane fraction and did not bind GIRK. Titrated expression of m-phosducin caused a reduction of A GIRK,basal by up to 90%. Expression of GIRK was accompanied by an increase in the level of G␤␥ and G␣ in the plasma membrane, supporting the existence of preformed complexes of GIRK with G protein subunits. Increased expression of G␤␥ and its constitutive association with GIRK may underlie the excessively high A GIRK,basal observed at high expression levels of GIRK. Only 10 -15% of A GIRK,basal persisted upon expression of both m-phosducin and c␤ARK. These results demonstrate that a major part of I basal is G␤␥-dependent at all levels of channel expression, and only a small fraction (<10%) may be G␤␥-independent.G protein-activated, inwardly rectifying K ϩ channels (GIRK, Kir3) 1 mediate postsynaptic inhibitory effects of various neurotransmitters in the brain and atrium via seven-helix, G protein-coupled receptors (GPCRs) linked to pertussis toxin-sensitive G proteins of the G i/o family. Opening of the channels is the result of a direct binding of G␤␥ subunits released from the G␣ i/o ␤␥ heterotrimers (1-4). The channel can also be activated by cytosolic Na ϩ and membranal phosphatidylinositol 4,5-bisphosphate (PIP 2 ); the latter is essential for proper GIRK gating by both Na ϩ and G␤␥ (3, 5, 6). Whereas the physiological role of neurotransmitter-induced GIRK activity is well established, the basal activity of these channels (A GIRK,basal ) is often regarded as negligible and physiologically unimportant. This feature distinguishes GIRK from many other K ϩ channels of the Kir family, such as Kir1 and Kir2, which show high intrinsic activity under physiological conditions and are often referred to as "constitutively active." Low A GIRK,basal is supposed to ensure high signal-to-noise ratio for GIRK-related neurotransmitter signaling and to minimize participation of GIRK in resting membrane K ϩ conductance (see Ref. 2). However, some classical and many recent studies challenge this concept. In sinoa...

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“…Transcripts for G protein-regulated inwardly rectifying K + channels (kcnj12), which play a role in regulation of heart rate (Nikolov and Ivanova-Nikolova, 2004), were up regulated on day 2, and may have resulted in hyperpolarization and a slowing of heart rate (Leaney et al, 2004). Inward rectifier potassium channels conduct currents at voltages around the reversal potential, and can stabilize the resting membrane potential and repolarize the myocyte (Kaibara et al, 2002).…”

Section: Histopathologymentioning

confidence: 99%

Critical Pathways in Heart Function: Bis(2-chloroethoxy)methane-Induced Heart Gene Transcript Change in F344 Rats

et al. 2006

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Gene transcript changes after exposure to the heart toxin, bis(2-chloroethoxy)methane (CEM), were analyzed to elucidate mechanisms in cardiotoxicity and recovery. CEM was administered to 5-week-old male F344/N rats at 0, 200, 400, or 600 mg/kg by dermal exposure, 5 days per week, for a total of 12 doses by study day 16. Heart toxicity occurred after 2 days of dosing in all 3 regions of the heart (atrium, ventricle, interventricular septum) and was characterized by myofiber vacuolation, necrosis, mononuclear-cell infiltration, and atrial thrombosis. Ultrastructural analysis revealed that the primary site of damage was the mitochondrion. By day 5, even though dosing was continued, the toxic lesions in the heart began to resolve, and by study day 16, the heart appeared histologically normal. RNA was extracted from whole hearts after 2 or 5 days of CEM dosing. After a screen for transcript change by microarray analysis, dose-response trends for selected transcripts were analyzed by qRT-PCR. The selected transcripts code for proteins involved in energy production, control of calcium levels, and maintenance of heart function. The down-regulation of ATP subunit transcripts (Atp5j, ATP5k), which reside in the mitochondrial membranes, indicated a decrease in energy supply at day 2 and day 5. This was accompanied by down-regulation of transcripts involved in high-energy consumption processes such as membrane transport and ion channel transcripts (e.g., abc1a, kcnj12). The up-regulation of transcripts encoding for temperature regulation and calcium binding proteins (ucp1 and calb3) only at the 2 low exposure levels, suggest that these adaptive processes cannot occur in association with severe cardiotoxicity as seen in hearts at the high exposure level. Transcript expression changes occurred within 2 days of CEM exposure, and were dose-and time-dependent. The heart transcript changes suggest that CEM cardiotoxicity activates protective processes associated energy conservation and maintenance of heart function.

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Coordination of Membrane Excitability through a GIRK1 Signaling Complex in the Atria

Cited by 54 publications

References 43 publications

Functional Characterization of a Small Conductance GIRK Channel in Rat Atrial Cells

Functional Characterization of a Small Conductance GIRK Channel in Rat Atrial Cells

Gβγ-dependent and Gβγ-independent Basal Activity of G Protein-activated K+ Channels

Critical Pathways in Heart Function: Bis(2-chloroethoxy)methane-Induced Heart Gene Transcript Change in F344 Rats

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