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Department of Pharmacology II, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
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Abstract |
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 Top Abstract IntroductionSummaryReferences |
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subunits released from pertussis toxin-sensitive G proteins, and contribute to neurotransmitter-induced deceleration of heart beat, formation of slow inhibitory postsynaptic potentials in neurones and inhibition of hormone release in endocrine cells. The physiological roles of KG channels are critically determined by mechanisms which regulate their activity and their subcellular localization. KG channels are tetramers of inward rectifier K+ (Kir) channel subunits, Kir3.x. The combination of Kir3.x subunits in each KG channel varies among tissues and cell types. Each subunit of the channel possesses one Gß binding site. The binding of Gß increases the number of functional KG channels via a mechanism that can be described by the Monod–Wyman–Changeux allosteric model. During voltage pulses KG channel current alters time dependently. The KG current exhibits inward rectification due to blockade of outward-going current by intracellular Mg2+ and polyamines. Upon repolarization, this blockade is relieved practically instantaneously and then the current slowly increases further. This slow current alteration is called ‘relaxation’. Relaxation is caused by the voltage-dependent behaviour of regulators of G protein signalling (RGS proteins), which accelerate intrinsic GTP hydrolysis mediated by the G
subunit. Thus, the relaxation behaviour of KG channels reflects the time course with which the G protein cycle is altered by RGS protein activity at each membrane potential. Subcellular localization of KG channels is controlled by several distinct mechanisms, some of which have been recently clarified. The neuronal KG channel, which contains Kir3.2c, is localized in the postsynaptic density (PSD) of various neurones including dopaminergic neurones in substantia nigra. Its localization at PSD may be controlled by PDZ domain-containing anchoring proteins. The KG channel in thyrotrophs is localized exclusively on secretary vesicles, which upon stimulation are rapidly inserted into the plasma membrane and causes hyperpolarization of the cell. This mechanism indicates a novel negative feedback regulation of exocytosis. In conclusion, KG channels are under the control of a variety of signalling molecules which regulate channel activity, subcellular localization and thus their physiological roles in myocytes, neurones and endocrine cells.
(Received 3 June 2003;
accepted after revision 12 August 2003;
first published online 15 August 2003)
Corresponding author Y. Kurachi: Department of Pharmacology II, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. Email: ykurachi{at}pharma2.med.osaka-u.ac.jp
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Introduction |
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TopAbstractIntroductionSummaryReferences |
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The next important step in this field was the discovery that pertussis toxin (PTX)-sensitive heterotrimeric G proteins (GK) were involved in the activation of the KACh channel by m2-muscarinic and A1-adenosine receptors (Pfaffinger et al. 1985; Breitwieser & Szabo, 1985; Kurachi et al. 1986a,b). The KACh channel, which also came to be known as the G protein-gated K+ (KG) channel, could be activated by intracellular GTP (GTPi) in the presence of agonists or by intracellular GTP S even in the absence of agonists. This could occur in cell-free, inside-out membrane patches in a membrane-delimited manner, suggesting that this channel was directly activated by G proteins (Kurachi et al. 1986a,b,c). Although some investigators reported that the subunits of G proteins (G) were the physiological activators of KG channels (Yatani et al. 1987, 1988), after a year-long controversy it was the ß subunits (Gß), and not G, which were shown to mediate the GK-induced activation of the channels (Logothetis et al. 1987; Kurachi et al. 1989, 1992; Ito et al. 1992; Yamada et al. 1993, 1994). This was confirmed with the molecular identification of the KG channel, which could functionally interact only with Gß, and not with G (Kubo et al. 1993; Dascal et al. 1993; Wickman et al. 1994; Reuveny et al. 1994; Krapivinsky et al. 1995; Inanobe et al. 1995).
The KG channel is usually a heterotetramer composed of subunits from the Kir3.x (x = 1–4) group of inward rectifier K+ (Kir) channels. Each subunit possesses one Gß binding site within the N- and C-terminal regions (Huang et al. 1995; Nishida & MacKinnon, 2002). Different combinations of Kir3.x subunits are found in different tissues and cells, e.g. the cardiac KG channel is composed of Kir3.1 and Kir3.4, whereas neuronal KG channels mainly exist as a hetero- or homo-tetramer containing Kir3.2. The primary structure of these subunits predicts two membrane-spanning regions (M1 and M2) and one potential pore-forming region (H5). The Glycine–Tyrosine–Glycine motif in the H5 region constitutes the selectivity filter for K+ ions (Doyle et al. 1998).
Recent progress in the physiology and molecular biology of KG channels has clarified their divergent functional roles in various organs. In this review, we will first describe the system of ACh activation of cardiac KG channels in the light of the latest knowledge, and then we will focus on recent advances in the control of localization and function of KG channels in various tissues.
Functional analysis of G protein activation of muscarinic K+ channels in cardiac atrial myocytes
The mechanism of how the KG channel is activated by Gß has been mainly investigated in inside-out patch membranes from atrial myocytes (Kurachi et al. 1986a; Ito et al. 1991, 1992). Figure 1A illustrates a concentration-dependent effect of GTPi in the presence or absence of ACh in the pipette. Figure 1B shows that as the concentration of ACh was increased, both the apparent potency and efficacy of GTPi were increased. The Hill coefficient for each response remained constant at about 3, irrespective of ACh concentration (Fig. 1B). Because the GTP-induced dissociation of G protein subunits is a one-to-one reaction (Gilman, 1987), positive cooperativity probably results from the interaction between GKß and the KG channel.
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. (ii) Each subunit has two distinct conformations: available (A) and unavailable (U). A and U bind GKß with dissociation constants KA and KU, respectively. A has higher affinity for GKß than U (i.e. KA < KU). (iii) All subunits in an oligomer must be in the same conformation (A or U) and change conformation simultaneously (i.e. An or Un). A and U are in equilibrium through an allosteric constant L. According to this model, an increase in GKß concentration leads to an increase in the fraction of A (i.e. A/(A+U)). The data shown in Fig. 1B can be fitted with this model by changing the assumed number of n. Such analysis indicates that n must be at least 4 to account for the data (Fig. 1D). This is consistent with the finding that Kir channels possess a tetrameric structure (Krapivinsky et al. 1995; Yang et al. 1995), and that one KG channel binds from one to four Gß subunits in native myocytes (Corey & Clapham, 2001). According to recent analysis of the crystal structure of the KG channel, the cytosolic (N- and C-terminal) region, which should interact with Gß, forms the ‘cytosolic pore’ (Nishida & MacKinnon, 2002). It may then be that this region is responsible for the slow gating mechanism of the KG channel.
A model for the receptor-mediated cyclic reaction of trimeric G proteins has been provided by Thomsen et al. (1988) (Fig. 1E). In native cardiac KG channels, as [ACh] is raised, the maximal channel activity induced by GTP becomes larger, and Kd for GTP decreases. These features are accounted for when Thomsen's formulation is incorporated into the MWC allosteric model (Hosoya & Kurachi, 1999) (Fig. 1B). From the fitted parameters, we have simulated the time courses both of the activation of KG channels upon application of 1 µM ACh and of deactivation after washout of the agonist. The simulated half-life for activation with 1 µM ACh was 
1 min, and that for deactivation was 2.5 min. This is much slower than the reaction measured in native cardiac KG channels, whose half-life for activation is 0.1–0.3 s and for deactivation is 0.6–1 s. This discrepancy may indicate that there exist further unidentified factors controlling KG channel activity.
RGS proteins are involved in physiological control of ACh activation of KG channels
Recently a family of cytosolic proteins which act as regulators of G protein signalling (RGS) has been identified (Hepler, 1999; Ross & Wilkie, 2000) (Fig. 2A). These proteins stabilize the transition state (G-GTP*) of GTP hydrolysis on the G subunit, which results in the acceleration of intrinsic GTPase activity (GTPase-accelerating protein; GAP). RGS proteins are supposed to play essential roles in the negative regulation of various G protein-mediated cell-signalling systems. In reconstituted systems using Xenopus oocytes or mammalian cell lines, RGS proteins have been reported to accelerate the time course of activation and deactivation of KG currents induced by agonists (Doupnik et al. 1997; Saito et al. 1997; Fujita et al. 2000) (Fig. 2B).
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5 nM (Fig. 2D). The relationship between channel activity and RGS concentration could be described by the incorporation of Thomsen's model into the MWC allosteric model (Y. Hosoya, M. Ishii & Y. Kurachi, unpublished observation). In Thomsen's model, the parameter indicating GTP hydrolysis, k6 was modified to the linear function of the concentration of RGS, as shown in the following equation:
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| (1) |
The simulated time courses for activation and deactivation of KG current in the presence of various concentrations of RGS are shown in Fig. 2E. In this simulation, RGS reduces maximal channel activity. The deactivation time course is accelerated by the presence of RGS, although the half-life is still longer than that of native cardiac KG current. On the other hand, no significant changes are detected in the activation time course, which seems to contradict several experimental results showing that RGS protein contributes to the acceleration of the activation time course. This discrepancy can be partly explained by the following facts.
Based on a biochemical measurement (Neubig et al. 1985), the concentration of G protein is assumed to be 100-fold greater than that of G protein-coupled receptor (GPCR), and thus more than 90% of G protein subunits always exist as the GDP-bound form in this model (Thomsen et al. 1988). Therefore, [G-GDP] can be practically constant over quite a wide range of GTPase activity originated by RGS proteins. Thus GTP hydrolysis is not the rate-limiting step for the activation phase of G protein and cannot account for the faster activation of KG current caused by the coexpression of RGS proteins. Further studies are needed to clarify the mechanism for the acceleration of the activation time course of KG current by RGS proteins.
Voltage-dependent relaxation gating of KG channels is caused by RGS proteins
K+ channels mediate K+ flux depending on the electrochemical gradient for K+ ions across the plasma membrane (Vm–EK; Vm, membrane potential; EK, K+ equilibrium potential) and channel conductance (gK). Thus, a macroscopic K+ current flowing through K+ channels can be expressed as follows:
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| (2) |
The G protein-gated K+ (KG) channel shows strong inward rectification. When the membrane potential is suddenly shifted from one voltage to another, the gK of the KG channel alters via two kinetically distinct processes. Upon hyperpolarization, gK increases instantaneously to a certain level and then increases slowly to the steady-state level (Fig. 3Aa). The reverse reaction, i.e. fast and slow decrease in gK, occurs upon membrane depolarization. The fast component is common to almost all Kir channels, whereas the slow component is characteristic of KG channels. Both slow and fast voltage-dependent gating properties of KG channels probably result from external factors because the channels lack any equivalent of the voltage-sensing S4 region of voltage-dependent K+ channels (Ho et al. 1993; Kubo et al. 1993).
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The slow component of the voltage-dependent change in gK of KG channels is called ‘relaxation’. This is characterized by a slow time-dependent current increase during hyperpolarizing pulses and reflects a slow recovery from inhibition at depolarized voltages by an unknown mechanism. Interestingly, this characteristic depends on the concentration of agonist (acetylcholine). Since it was first described in sino-atrial node cells (Noma & Trautwein, 1978), the molecular mechanism underlying this characteristic feature of the KG current has been an enigma. KG currents reconstituted in Xenopus oocytes by expressing Kir3.1/Kir3.4 and m2R do not exhibit relaxation. We found that coexpression of RGS protein was mandatory for reconstituting the relaxation behaviour of the KG current (Fujita et al. 2000), and this effect was mediated exclusively by the interaction of the RGS domain of the RGS protein with the PTX-sensitive G subunit (Inanobe et al. 2001). It was, however, still unclear how the cytosolic RGS protein conferred voltage dependence on the KG current.
Further investigation in our laboratory has revealed that the relaxation of native KG channel currents in cardiac myocytes could result from depolarization facilitating RGS and decreasing KG channel availability (Figs 3A and B) (Ishii et al. 2001, 2002). At diastolic membrane potentials the GAP action of RGS proteins is inhibited by phosphatidylinositol-3,4,5-trisphosphate (PIP3). Binding of Ca2+–calmodulin (CaM) to RGS relieves PIP3-mediated inhibition, restores the GAP activity of RGS proteins, and decreases free Gß and thus the number of active KG channels. The Ca2+–CaM complex is formed by depolarization-induced Ca2+ influx across the plasma membrane (Fig. 3B). Therefore, at systolic membrane voltages the G protein cycle is negatively regulated and the number of active KG channels is decreased. Thus ‘relaxation’ turns out not to be a gating process but a biochemical reaction between RGS and G proteins (Fig. 3C). In this context the KG channel can be regarded as only an example of G protein-effector molecules through which we can detect the G protein cycle in real time with high temporal resolution. The principle proposed here therefore should not be limited only to the KG channel system, but must also be applicable to other G protein-signalling machinery controlling such target proteins as neuronal (N-, P/Q-type) Ca2+ channels, phospholipase C and adenylyl cyclases. Considering that more than 20 members of the RGS protein family are differentially expressed in a tissue- or cell-specific manner and that only some of them are subject to allosteric regulation by CaM–PIP3 (M. Ishii & Y. Kurachi, unpublished observation), the mode of action of RGS on the G protein cycle in various tissues should be divergent, which may contribute to fine tuning of G protein-mediated cell signalling.
Control of subcellular localization of KG channels
The specific localization of membrane proteins is one of the most important mechanisms for determining their functional roles. A family of PDZ domain-containing anchoring proteins such as PSD-95 and SAP-97 has emerged as one of the major players in anchoring membrane-associated proteins and scaffolding signalling molecules (Sheng & Sala, 2001). The localization and function of Kir2.3, Kir3.2, Kir4.1 and Kir5.1 are determined by PDZ proteins (Cohen et al. 1996; Horio et al. 1997; Hibino et al. 2000; Tanemoto et al. 2002).
Kir3.2 is a KG channel subunit which is predominantly expressed in neurones where KG channels are mainly composed of heterotetramers of Kir3.1 and Kir3.2. Kir3.2 possesses several splicing variants, Kir3.2a-d. Dopaminergic neurones in the substantia nigra contain only Kir3.2a and Kir3.2c (Inanobe et al. 1998) and their KG channels may be either heteromers of Kir3.2a and Kir3.2c or homomers of Kir3.2c. Kir3.2c is a particular KG channel subunit because it possesses a PDZ protein binding motif (-Glu-Ser-Lys-Val) in its C-terminus. No KG channel currents could be recorded in Xenopus oocytes expressing Kir3.2c and G protein-coupled receptors unless SAP-97 was coexpressed (Hibino et al. 2000). The PDZ domain-containing anchoring proteins may therefore play a crucial role not only in the regulation of localization but also in the modulation of the function of KG channels which contain the Kir3.2c subunit.
Subcellular localization of KG channels may also be regulated in a tissue-specific manner. The KG channels of both atrial myocytes and thyrotrophs of anterior pituitary lobes are composed of Kir3.1 and Kir3.4 subunits. The subcellular localization of heteromeric Kir3.1/Kir3.4 channels in these tissues are, however, completely different. Cardiac KG channels are localized on the cell membrane, whereas KG channels in resting thyrotrophs are found exclusively on intracellular secretary vesicles (Morishige et al. 1999). The stimulation of thyrotrophs with thyrotropin-releasing hormone (TRH) causes the fusion of secretary vesicles to the plasma membrane and enhancement of dopamine- or somatostatin-induced KG current (Fig. 4). This novel mechanism for the rapid insertion of functional ion channels into the plasma membrane may contribute to forming an effective negative feedback control loop for hormone secretion by hyperpolarizing the membrane potential. A similar feedback mechanism might be present in the nervous system where some KG channels are known to be localized on the presynaptic region of neuronal axonal termini (Morishige et al. 1996).
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Summary |
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Footnotes |
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References |
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 T. Wieland and S. Herzig Specificity and Diversity in Gi/o-Mediated Signaling: How the Heart Operates the RGS Brake Pedal Circ. Res., March 17, 2006; 98(5): 585 - 586. [Full Text] [PDF]
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 L. Koyrakh, R. Lujan, J. Colon, C. Karschin, Y. Kurachi, A. Karschin, and K. Wickman Molecular and Cellular Diversity of Neuronal G-Protein-Gated Potassium Channels J. Neurosci., December 7, 2005; 25(49): 11468 - 11478. [Abstract] [Full Text] [PDF]
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I. Rishal, Y. Porozov, D. Yakubovich, D. Varon, and N. Dascal G{beta}{gamma}-dependent and G{beta}{gamma}-independent Basal Activity of G Protein-activated K+ Channels J. Biol. Chem., April 29, 2005; 280(17): 16685 - 16694. [Abstract] [Full Text] [PDF]
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E. L. Riddle, R. A. Schwartzman, M. Bond, and P. A. Insel Multi-Tasking RGS Proteins in the Heart: The Next Therapeutic Target? Circ. Res., March 4, 2005; 96(4): 401 - 411. [Abstract] [Full Text] [PDF]
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