The role of maxiK channels in carotid body chemotransduction

https://doi.org/10.1016/j.resp.2006.10.010Get rights and content

Abstract

MaxiK channels are a unique class of K+ channels activated by both voltage and intracellular Ca2+. Derived from a single gene, their diversity arises from extensive splicing, and their wide distribution has led to their implication in a large variety of cellular functions. In the carotid body, they have been proposed to contribute to the resting membrane potential of type I cells, and also to be O2 sensitive. Thus, they have been suggested to have an important role in hypoxic chemotransduction. Their O2 sensitivity is preserved when the channels are expressed in HEK 293 cells, permitting detailed studies of candidate mechanisms underlying hypoxic inhibition of maxiK channels. In this article, we review evidence for and against an important role for maxiK channels in chemotransduction. We also consider different mechanisms proposed to account for hypoxic channel inhibition and suggest that, although our understanding of this important physiological process has advanced significantly in recent years, there remain important, unanswered questions as to the importance of maxiK in carotid body chemoreception.

Introduction

It is rapidly approaching the twentieth anniversary of the publication of a paper which provided a significant turning point in peoples’ views of potential mechanisms underlying the process of carotid body chemotransduction. In the late 1980s researchers in Valladolid and Seville combined forces to analyse the effects of hypoxia on ionic channels expressed by type I cells of the rabbit carotid body. In their seminal paper (Lopez-Barneo et al., 1988), these workers reported that hypoxia reversibly and selectively inhibited whole-cell K+ currents in these cells. In so doing, they laid the foundations for what has become known as the membrane hypothesis of chemotransduction. This hypothesis has been described, discussed, dissected and revised in numerous detailed reviews elsewhere (Gonzalez et al., 1992, Gonzalez et al., 1994, Lopez-Barneo et al., 1993, Lopez-Barneo et al., 2001, Peers and Buckler, 1995) so we shall not go into this in any depth; suffice to say, hypoxic inhibition of K+ channels in type I cells leads to their depolarization. This activates voltage-gated Ca2+ channels and the subsequent influx of Ca2+ triggers neurotransmitter release to activate afferent chemosensory fibres of the carotid sinus nerve.

Within a brief period of time, researchers from the UK (Duchen et al., 1988, Peers, 1990c) Germany (Hescheler et al., 1989) and Canada (Stea and Nurse, 1991) had followed suit with reports of ion channels in type I cells and their responses to hypoxia as well as other chemostimuli. These reports, together with later studies (Buckler, 1997, Perez-Garcia et al., 2004) have added both to our understanding of, and to our confusion concerning, the membrane hypothesis. Of the many aspects of the hypothesis over which there is confusion and debate, the longest standing is the molecular identity of the K+ channel which is inhibited by hypoxia. All of the above reports indicated that multiple types of K+ channels are expressed in type I cells, but the specific identity of the O2-sensitive K+ channel is contested. Some of this confusion arose from the fact that different research groups were isolating type I cells from different species (rabbit versus rat, and more recently cat (Shirahata and Sham, 1999) and mouse (Perez-Garcia et al., 2004, Yamaguchi et al., 2004) carotid bodies have been employed) and from animals of different ages (embryonic (Hescheler et al., 1989) versus adult (Ganfornia and Lopez-Barneo, 1991)). Currently, it would appear that the O2 sensitive K+ channels in mouse and rabbit belong to the Kv3 and Kv4 subfamilies, respectively (Sanchez et al., 2002, Perez-Garcia et al., 2004). By contrast, two distinct O2 sensitive K+ channels in the rat have been identified. Using neonatal rat type I cells, a TASK-like, tandem-P domain “leak” K+ channel has been identified in more recent times (Buckler, 1997). However, originally a high-conductance, voltage-and Ca2+-sensitive K+ channel (BK, or maxiK) channel was identified in these cells (Peers, 1990c). Subsequent work also identified maxiK channels as O2 sensitive in adult rat cells (Lopez-Lopez et al., 1997). This review focuses on maxiK channels and their O2 sensitivity. Our aim is to give a reasoned and hopefully objective view as to their importance in chemotransduction, and what we currently understand of the mechanisms coupling hypoxia to maxiK inhibition.

Section snippets

MaxiK channel structure and regulation

MaxiK channels are widely distributed channels which share the commonalities of being both voltage- and Ca2+-gated and having a seemingly paradoxically high selectivity for K+, yet a high conductance. Their basic topology is shown in Fig. 1. Like other voltage-sensing K+ channels, maxiK α subunits have six transmembrane α helices (S1–S6), the fourth of which contains charged residues required for voltage-sensing. The P loop region between helicies S5 and S6 composes the lining of the pore when

MaxiK channels in the carotid body

In the early years of carotid body patch-clamp electrophysiology, when type I cells were isolated only from rat or rabbit tissue, maxiK channels were found in both species (Peers, 1990c, Ganfornina and Lopez-Barneo, 1992), but only really studied in depth in rat type I cells, since they are not O2 sensitive in rabbit, at least in excised patches (Ganfornina and Lopez-Barneo, 1992). Initially, whole-cell recordings revealed K+ current–voltage-recordings with a distinctive outward “shoulder” at

Are maxiK channels important in hypoxic chemotransduction?

Our initial suggestion that maxiK were active at, and so contributed to maintenance of, type I cells’ resting membrane potential has not been fully accepted, and alternative candidates for determinants of resting membrane potential have been put forward. Most notably, Buckler has identified a voltage-insensitive, TASK-like K+ conductance in rat type I cells (Buckler, 1997), and rabbit type I cells show spontaneous electrical activity (Montoro et al., 1996), which brings into play the

Mechanisms of hypoxic inhibition of maxiK channels

Ever since the discovery of hypoxic regulation of K+ (and other) channels, researchers have debated and speculated about possible mechanisms to account for such an effect. The reader will find detailed information concerning some of these in other chapters of this issue. Here, we would like to consider each of these briefly, and also the question of whether or not such proposed mechanisms can conceivably co-exist. A summary cartoon of these mechanisms is shown in Fig. 6. Perhaps the highest

Future prospects

Whilst the available pieces of evidence are not decisive, they do point to a likely direct involvement of maxiK in O2 sensing by the carotid body. However, before we can be certain as to the importance of the role of maxiK, some key questions remain to be addressed. Most fundamentally, does the maxiK channel contribute to type I cell resting membrane potential under physiological conditions (i.e. in situ)? Any contribution to membrane potential will depend on which splice variant(s) is/are

Acknowledgements

The work described in this paper to which the authors have contributed has often been conducted in collaboration with numerous colleagues with all of whom it has been a pleasure to work. Financial support has come from The Wellcome Trust and the British Heart Foundation.

References (56)

  • R. Schubert et al.

    Protein kinases: tuners of the BKCa channel in smooth muscle

    Trends Pharmacol. Sci.

    (2001)
  • S. Yamaguchi et al.

    Patch clamp study of mouse glomus cells using a whole carotid body

    Neurosci. Lett.

    (2004)
  • M.M. Zarei et al.

    A novel MaxiK splice variant exhibits dominant-negative properties for surface expression

    J. Biol. Chem.

    (2001)
  • K.J. Buckler et al.

    Effects of hypoxia on membrane potential and intracellular calcium in rat neonatal carotid body type I cells

    J. Physiol.

    (1994)
  • K.J. Buckler

    A novel oxygen-sensitive potassium channel in rat carotid body type I cells

    J. Physiol.

    (1997)
  • K.J. Buckler et al.

    Effects of extracellular pH, pCO2 and HCO3-on intracellular ph in isolated type I cells of the neonatal rat carotid-body

    J. Physiol.

    (1991)
  • D.H. Cox

    The BKCa channel's Ca2+-binding sites, multiple sites, multiple ions

    J. Gen. Physiol.

    (2005)
  • D.F. Donnelly

    Modulation of glomus cell membrane currents of intact rat carotid body

    J. Physiol.

    (1995)
  • F. Duprat et al.

    TASK, a human background K+ channel to sense external pH variations near physiological pH

    EMBO J.

    (1997)
  • C. Eyzaguirre

    Chemical and electric transmission in the carotid body chemoreceptor complex

    Biol. Res.

    (2005)
  • A. Ganfornia et al.

    Single potassium channels in membrane patches of arterial chemoreceptor cells are modulated by oxygen tension

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

    (1991)
  • A. Ganfornina et al.

    Potassium channel types in arterial chemoreceptor cells and their selective modulation by oxygen

    J. Gen. Physiol.

    (1992)
  • C. Gonzalez et al.

    Carotid body chemoreceptors: from natural stimuli to sensory discharges

    Physiol. Rev.

    (1994)
  • F.K. Green et al.

    Intracellular acidosis inhibits Ca2+-dependent K+-currents in isolated type-i cells of the neonatal rat carotid-body

    J. Physiol.

    (1990)
  • C.J. Hatton et al.

    Developmental changes in isolated rat type i carotid body cell K+ currents and their modulation by hypoxia

    J. Physiol.

    (1997)
  • A. Jackson et al.

    Dopaminergic properties of cultured rat carotid body chemoreceptors grown in normoxic and hypoxic environments

    J. Neurochem.

    (1997)
  • J. Ledoux et al.

    Calcium-activated potassium channels and the regulation of vascular tone

    Physiology (Bethesda)

    (2006)
  • A. Lewis et al.

    Hypoxia inhibits human recombinant maxi K+ channels by a mechanism which is membrane delimited and Ca2+ sensitive

    J. Physiol.

    (2002)
  • Cited by (42)

    • Carotid chemoreceptor “resetting” revisited

      2013, Respiratory Physiology and Neurobiology
    • Neuroepithelial cells of the gill and their role in oxygen sensing

      2012, Respiratory Physiology and Neurobiology
    • Carbon monoxide (CO) and hydrogen sulfide (H<inf>2</inf>S) in hypoxic sensing by the carotid body

      2012, Respiratory Physiology and Neurobiology
      Citation Excerpt :

      These observations suggest that endogenous CO is a physiological inhibitor of the carotid body sensory activity. A major advance in the carotid body research is the demonstration that hypoxia inhibits certain K+ channels in glomus cells resulting in depolarization, leading to activation of voltage-gated Ca2+ channels and Ca2+ influx (see Peers and Wyatt, 2007; Kumar and Prabhakar, 2012 for ref). Peers (1990) identified Ca2+-activated K+ channel (maxi K) as one of the targets of hypoxia in glomus cells.

    • Chronic hypoxia in cultured human podocytes inhibits BK <inf>Ca</inf> channels by upregulating its β4-subunit

      2012, Biochemical and Biophysical Research Communications
      Citation Excerpt :

      However, we have not yet ruled out other mechanisms, such as subunit translation, trafficking, assembly, or a combination of these processes, which could provide a powerful stimulus for functional BKCa channel remodeling. It has been proposed that the hypoxic-induced inhibition of BKCa channels contributes to the activation of voltage-gated Ca2+ channels through their depolarization in many cell types, such as the carotid body and central neurons [13]. However, podocytes do not express voltage-gated Ca2+ channels [34].

    • Characterization of an ATP-sensitive K<sup>+</sup> channel in rat carotid body glomus cells

      2011, Respiratory Physiology and Neurobiology
      Citation Excerpt :

      Initiation of excitation of CB cells by hypoxia is caused in large part by inhibition of background K+ channels that allow cell depolarization to occur as a result of a resting a Na+ conductance (Buckler, 2007; Carpenter and Peers, 2001). K+ channels that give rise to the O2-sensitive background K+ conductance have generally been described to be TASK, BK and/or KV channels (Buckler et al., 2000; Lopez-Barneo et al., 2004; Lopez-Lopez and Perez-Garcia, 2007; Peers and Wyatt, 2007). In isolated rat CB cells, TASK is the most active K+ channel near the resting membrane potential, and is inhibited by hypoxia (Buckler et al., 2000; Kim et al., 2009).

    View all citing articles on Scopus
    View full text