A structural motif in the C-terminal tail of slo1 confers carbon monoxide sensitivity to human BKCa channels

Williams, Sandile E; Brazier, Stephen P.; Baban, Nian; Telezhkin, Vsevolod; Müller, Carsten T.; Riccardi, Daniela; Kemp, Paul J.

doi:10.1007/s00424-007-0439-4

Cited by 49 publications

(65 citation statements)

References 27 publications

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“…However, how heme binds and whether CO stimulates K ϩ efflux in a heme-dependent or heme-independent manner has still to be established. A cytochrome c-type CXXCH motif is present rather than the typical HRM (45)(46)(47)(48). Further studies are also required to establish the physiological relevance of the apparent heme-mediated inhibition of the arginine transferase activity of R-transferase and of putative heme binding to stanniocalcin glycoprotein hormones (52)(53)(54).…”

Section: Non-nr Heme Sensorsmentioning

confidence: 99%

“…Studies on a peptide containing the CXXCH motif (which binds heme by His coordination) led to a conclusion that heme is the CO-binding site (45). However, mutating the CXXCH motif His did not diminish the effect of CO on channel permeability (despite heme loss), possibly because CO might also interact with an unidentified metal cluster (46,47). It was also proposed that BK channels do not bind heme but that CXXCH motif cysteines form a thiol/disulfide redox switch, similar to that proposed for Rev-erb␤ (48).…”

Section: Cellular Homeostasismentioning

confidence: 99%

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Heme Sensor Proteins

Girvan

Munro

2013

Journal of Biological Chemistry

128

116

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Heme is a prosthetic group best known for roles in oxygen transport, oxidative catalysis, and respiratory electron transport. Recent years have seen the roles of heme extended to sensors of gases such as O 2 and NO and cell redox state, and as mediators of cellular responses to changes in intracellular levels of these gases. The importance of heme is further evident from identification of proteins that bind heme reversibly, using it as a signal, e.g. to regulate gene expression in circadian rhythm pathways and control heme synthesis itself. In this minireview, we explore the current knowledge of the diverse roles of heme sensor proteins. Heme-responsive Proteins: Defining FeaturesHeme homeostasis is crucial. Free heme at Ͼ1 M is cytotoxic, mainly by producing reactive oxygen species. Iron intake accounts for only a small proportion of mammalian requirements, so iron recycling (particularly from heme) is critical (1). Tight regulation of heme synthesis/breakdown is needed. Heme regulates its own fate and controls several other biological processes. Heme-responsive proteins elicit cellular responses by binding/debinding heme or via changes in heme ligation (e.g. by gases) or redox state. They can be divided into two classes: nuclear receptor (NR) 2 hemoproteins and heme sensors with no NR function. Each heme-responsive protein has a heme regulatory motif (HRM), usually containing a CP motif (2). The Cys residue of the CP motif is an axial heme ligand. No other residues are conserved across the protein class. The wider relevance of the CP motif is unclear because other hemoproteins (e.g. prostaglandin E 2 synthase, chloroperoxidase, and some cytochromes P450) also have a CP motif. The properties of members of the two main classes are described below. NR HemoproteinsSeveral heme-binding proteins occur in the NR superfamily, which is the largest transcription factor superfamily (summarized in Table 1). NRs bind specific DNA motifs in response to small molecule signaling. They generally share conserved domain architecture, with a DNA-binding region containing two zinc fingers, a ligand-binding domain, and activation domains (3). Usually, ligand binding induces conformational changes that dissociate partner proteins, allowing DNA binding and/or changes to dimerization status or cellular localization that enable the protein to elicit a response. A subfamily of NRs binds heme at their ligand-binding domain and so act as heme sensors, as discussed below. Circadian Rhythm Heme SensorsCircadian rhythms are regulated by feedback loops at transcriptional/translational levels. Heme is critical in this process (4). In vertebrates, the expression of several day/night cycle genes, as well as Rev-erb␣, is controlled by binding a heterodimer of Clock (or NPAS2 (neuronal PAS domain protein 2)) and Bmal1 to their 5Ј-UTR, thus switching on transcription. Expression of Bmal1 and NPAS2/Clock is repressed in turn by binding of Rev-erb␣ to a homodimeric partner (5). Rev-erb␣ and homologs (Rev-erb␤ and E75, with the latter involved in inse...

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Section: Non-nr Heme Sensorsmentioning

confidence: 99%

Section: Cellular Homeostasismentioning

confidence: 99%

Heme Sensor Proteins

Girvan

Munro

2013

Journal of Biological Chemistry

128

116

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“…Conversely, the upregulation of the channel function in specific cell types may offer protection against some of the aforementioned disorders [107][108][109][110]. The BK Ca channel activity is subjected to modulation by a wide spectrum of biologically relevant factors such as Ser/Thr/Tyr phosphorylation, Cys/Met oxidation, steroid hormones, and diatomic gases (O 2 , NO, and CO) [111][112][113][114]. The PKG-dependent activation of the Na þ /Ca 2þ exchanger by CO has been proposed [12]: this may increase the submembrane Ca 2þ concentration in the vicinity of the BK Ca channels with their consequential opening [115].…”

Section: Co Signalingmentioning

confidence: 99%

“…In addition to the PKG-dependent mechanism, it has been suggested that CO directly stimulates BK Ca channels, implicating that the channels themselves are gas sensors [116]. CO, administrated as a gas or as CO-releasing molecules (CORMs) [117], increases the probability of channel opening [118][119][120] even in cell-free membrane patches [112,114,121], thus suggesting the possibility that CO modulates the channel directly or indirectly through entities intimately associated with the channel proteins, possibly in the same macromolecular complex [116].…”

Section: Co Signalingmentioning

confidence: 99%

CO metabolism, sensing, and signaling

et al. 2011

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Abstract.CO is a colorless and odorless gas produced by the incomplete combustion of hydrocarbons, both of natural and anthropogenic origin. Several microorganisms, including aerobic and anaerobic bacteria and anaerobic archaea, use exogenous CO as a source of carbon and energy for growth. On the other hand, eukaryotic organisms use endogenous CO, produced during heme degradation, as a neurotransmitter and as a signal molecule. CO sensors act as signal transducers by coupling a ''regulatory'' heme-binding domain to a ''functional'' signal transmitter. Although high CO concentrations inhibit generally heme-protein actions, low CO levels can influence several signaling pathways, including those regulated by soluble guanylate cyclase and/or mitogenactivated protein kinases. This review summarizes recent insights into CO metabolism, sensing, and signaling.

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“…There are many proposed cellular targets of CO including soluble guanylate cyclase (sGC) [24] and mitogen-activated protein kinases (for review, see [25]). Recent experiments have also shown CO to play important roles in cardiovascular function [26] and O 2 sensing [27,28] via an activation of large-conductance, calcium-activated potassium channel (BK Ca ). Other ion channels have also been shown to be modulated by CO such as L-type calcium channels (Ca v 1.2) [29], TREK-1 [30] and ENaC channels [31].…”

Section: Introductionmentioning

confidence: 99%

The carbon monoxide donor, CORM-2, is an antagonist of ATP-gated, human P2X4 receptors

Wilkinson

Kemp

2011

Purinergic Signalling

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Carbon monoxide (CO) is produced endogenously by heme oxygenase (HO) enzymes. HO-1 is highly expressed in many inflammatory disease states, where it is broadly protective. The protective effects of HO-1 expression can be largely mimicked by the exogenous application of CO and CO-releasing molecules (CORMs). Despite a dearth of pharmacological tools for their study, molecular methodologies have identified P2X4 receptors as a potential anti-nociceptive drug target. P2X4 receptors are up-regulated in animal models of inflammatory pain, and their knockdown reduces pain behaviours. In these same animal models, HO-1 expression is anti-nociceptive, and we therefore investigated whether P2X4 was a target for CO and tricarbonyldichlororuthenium (II) dimer (CORM-2). Using conventional whole-cell and perforated-patch recordings of heterologously expressed human P2X4 receptors, we demonstrate that CORM-2, but not CO gas, is an inhibitor of these channels. We also investigated the role of soluble guanylate cyclase and mitochondria-derived reactive oxygen species using pharmacological inhibitors but found that they were largely unable to affect the ability of CORM-2 to inhibit P2X4 currents. A control breakdown product of CORM-2 was also without effect on P2X4. These results suggest that P2X4 receptors are not a molecular target of endogenous CO production and are, therefore, unlikely to be mediating the anti-nociceptive effects of HO-1 expression in inflammatory pain models. However, these results show that CORM-2 is an effective antagonist at human P2X4 receptors and represents a useful pharmacological tool for the study of these receptors given the current dearth of antagonists.

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A structural motif in the C-terminal tail of slo1 confers carbon monoxide sensitivity to human BKCa channels

Cited by 49 publications

References 27 publications

Heme Sensor Proteins

Heme Sensor Proteins

CO metabolism, sensing, and signaling

The carbon monoxide donor, CORM-2, is an antagonist of ATP-gated, human P2X4 receptors

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