voltage-dependent chloride channels: invertebrates to man

THE JOURNAL OF EXPERIMENTAL ZOOLOGY 275~277-282 (1996)

Voltage-Dependent Chloride Channels: Invertebrates to Man

CRAIG H. GELBAND, PHILLIP G. GRECO, AND JEFFREY R. MARTENS Department of Physiology, College of Medicine, University of Florida, Gainesville, Florida 3261 0

ABSTRACT Chloride channels are ubiquitous proteins found in invetebrates to man. C1- is one of the most abundant biological anions and accounts for a measurable fraction of the electrical conductance of many biological membranes. Physiologically this contributes to cellular processes, including pH regulation, volume regulation, generation of the resting membrane potential, and regulation of membrane excitability. The unitary conductance of voltage-dependent C1- channels is as diverse as the number of different types of C1- channels described ranging from 5-450 pS. C1- channels are highly anion selective passing at least ten anionic species, including all of the halides. C1- channels are blocked by various agents, including aromatic acids, inorganic cations, and protons. Maintaining high resting conductance and normal excitability, regulating cell volume, and modulating hormone action are some examples of the functions of C1- channels. Despite the large amount of data accumulated on voltage-dependent C1- channels, identifying subsets within this class of channels with coherent biophysical features that subserve each specific function is still not possible. At present, the molecular structure for every type of functional Cl- channels has not been determined, but future identification of cloned Cl- channel structures should provide a clearer understanding of the functional properties of background C1- channels. @ 1996 WiIey-Liss, Inc.

The chloride ion (Cl-) has been assigned an unspecialized role in ion homeostatis of the cell. This view came from studies of the resting C1- conductance in frog skeletal muscle and red blood cells, in which C1- is passively distributed across the plasma membrane and equilibrates rapidly. C1- is one of the most abundant biological anions and accounts for a measurable fraction of the electrical conductance of many biological membranes. Electrophysiological studies using single- channel recording methods (Hamill et al., '81) have shown that C1- channels exist in many cell types. These channels have been found in the plasma and intracellular membranes of nearly every type of cell examined. However, their distribution in lower organisms is poorly documented, This is due to the few numbers of studies of the electrical properties of membranes in lower animals relative to higher vertebrates. Caz+ ions, a report has been made of C1--dependent action potentials in chick skeletal muscle cells (Fukuda, '74).

A wide variety of cells exhibits a nonequilibrium distribution of C1- ions across the plasma membrane (Hille, '94). Physiologically this contributes to cellular processes, including pH regulation, volume regulation, generation of the resting membrane potential, and regulation of membrane excitability. Many types of C1- channels have been 0 1996 WILEY-LISS, INC.

described in mammalian cells. This chapter focuses on the characteristics of the voltage-dependent C1- channels of the plasma membrane. These channels have been characterized only recently. The presumed physiological irrelevance of C1- channels caused them to be ignored. During the three decades after the classical description of the action potential in squid axon by Hodgkin and Huxley ('521, membrane excitation and neural transmission seemed to be explained solely by the interplay of Na', K, and Ca2' currents. This re- view focuses primarily on the ionic permeation, gating, and pharmacological properties of voltage- dependent C1- channels.

CELLULAR DISTRIBUTION Information about voltage-dependent C1- chan-

nel distribution is limited primarily due to the lack of high-affinity marker ligands for C1- channels. Patch-clamp studies showed that C1- channels are regularly detected in the sarcolemma of nonverte- brate and vertebrate cellular preparations. In lower

Received and accepted March 13, 1996. Address reprint requests to Craig H. Belgand, Department of Physi-

ology, University of Florida College of Medicine, p.0. Box 100274, Gainesville, FL 32610.

278 C.H. GELBAND ET AL.

organisms, for example, voltage-dependent C1- channels have been demonstrated in the Cyanea jellyfish (Anderson and McKay, '851, Ascaris nematode (Thorn and Martin, ,871, mollusks (Geletyuk and Kazachenko, '85; Khalsa et al., '901, Aplysia (Chesnoy-Marcahis and Evans, '86), and lobster nerve (Lukacs and Moczyd- lowski, '90). In higher animals, voltage-dependent C1- channels hake been illustrated in rat hippocampal cells (Franciolini and Nonner, '87; Shukla and Pockett, 'go), cerebral astrocytes (Sonnhof, '871, Schwann cells (Gray et al., '84), aorta (Soejima and Kokobun, '881, and heart (Cuolombe et al., '871, in rabbit bladder (Han- rahan et al., '85), in mouse lymphocytes (Bosma, '891, and astrocytes (Nowak et al., '871, and in human skeletal muscle (Fahlke et al., '92), epithelial cells (Welsh, '861, and lymphocytes (Schlicter et al., '90).

IONIC PERMEATION Conductance

The unitary conductance of voltage-dependent C1- channels is as diverse as the number of different types of C1- channels described. Therefore, unitary conductance cainnot be used as an identifying characteristic of hackground C1- channels. Unitary conductances, as measured with the patch-clamp method, span about two orders of magnitude from the 5 pS conductance of the hyperpolarization-activatcbd C1- channel in mouse astrocytes (Nowak et al., '87) to the 450 pS conductance of the large conductance C1- channel of rat Schwann cells (Gray et al., '84). For a detailed description of the conductances, permeation properties, and pharmacology of C1- channels, refer to Franciolini and Adanis ('94).

Current-voltage (I-V) .relations of voltage-dependent C1- channels show outward rectification. This effect cannot be explained by an increase in the open probability of the channel at positive voltages, since the I-V plots are obtained from single- channel measurements. Rectification is more likely a result of asymmetries of charged residues in the ionic permeation pathway of the channel pore; however, studies have not addressed this point specifically (Franciolini and Adams, '94). Another common occurrence in voltage-dependent C1- channels is the presence of subconductance states. Subconductance levels have been found in chloride channels from IPorpedo electroplax organ, molluscan neurons, rat astrocytes, mouse B lymphocytes, and amphibian skeletal muscle (Fox, '87).

Selectivity Voltage-dependent C1- channels are highly an-

ion selective. C1- channels pass at least ten anionic species, including all of the halides. Although Br-, I-, NO3-, and SCN- are more permeant than C1-, the channel is termed C1- channel because, under physiological conditions, Cl- is the most rel- evant anion. Despite the large diversity of C1- channel conductance, the ionic selectivity se- quences for these channels are similar: an inverse relationship exists between the crystal diameter of the ions and their permeability ratios (Franciolini and Adams, '94). The permeability of several voltage-dependent C1- channels to hydrophobic (benzoate, glutamate) anions, as well as the blocking action brought about by a number of aromatic compounds (5-nitro-2-(3-phenylpropylamino) benzoate (NPPB) and anthracene-9 carboxylate [9-ACl, suggests the presence of a hydrophobic region in the channels.

The C1- channel selectivity data also provide an estimate of the lower limit for possible channel cross-sections. All permeant anions tested can fit through a 6-A diameter pore, provided that some of the organic anions align their long axis with the channel. This minimal pore size is very close to the dimensions proposed for the endplate channel (6.5 x 6.5 A [Dwyer et al., 'Sol), a weakly selective cation channel, but is larger than that of the more selective Na' and K+ channels (3.1 x 5.1 A and 3.3 x 3.3 A, respectively [Hille, '941). Another observation made from these ion selectivity experiments is that voltage-dependent C1- channels show signifcant permeability to alkali cations as well. This finding is an anomaly and contradicts experience with cation channels, of which none has been found to leak anions. The observation that voltage-dependent C1- channels can be significantly permeable to cations could cre- ate a physiological problem. C1- channels, if permeable to cations under physiological conditions, should destabilize the membrane resting potential (by allowing Na' in) rather than stabilize it, as is actually observed (Franciolini and Adams, '94). Franciolini and Nonner ('87) made the fol- lowing observations. First, although cations were permeant through the open channel, they could not pass the absence of a permeant anion. Sec- ond, the total permeation rate depended on the species of cation present. These observations in- dicated a strong interdependence between anion and cation fluxes in the channel (Franciolini and Nonner, '87).

VOLTAGE-DEPENDENT CL- CHANNELS 279

C1- CHANNEL GATING Voltage-dependent background C1- channels can

be grouped into three categories based on their voltage sensitivities: 1) channels activated by hyperpolarization, 2) channels activated by depolarization, and 3) channels inactivated by polarization away from 0 mV.

Hyperpolarization-activated channels Hyperpolarization-activated C1- currents were

first observed in Aplysia neurons (Chesnoy- Marchais, '82). Activation is generally slow, with a time constant of several hundred milliseconds. The gating properties of the channel, analogous to the hyperpolarization-activated (inward recti- fier) K+ current (Hagiwara et al., '76), depend on the intracellular C1- concentration (Chesnoy- Marchais, '83). Increasing the internal C1- concentration lowers the activation threshold and accelerates the activation kinetics. Functionally, this behavior would facilitate extrusion of excess intracellular C1-. The hyperpolarization-activated C1- channel has been identified and characterized at the single-channel level. This channel has three subconductance states, with a maximal conductance of 10-15 pS (Chesnoy-Marchais and Evans, '86), similar to that observed for the double-barreled C1- channel (Miller and Richard, '90). The double-barreled C1- channel from Torpedo is also activated by hyperpolarization. Steady-state macroscopic conductance, measured in planar lipid bilayers containing on the order of 103 C1- channels, is low at positive voltages and increases with hyperpolarization. Another background C1- channel activated by hyperpolarization has been reported by Nowak et al. ('87) in cultured mouse astrocytes. The study, carried out on outside-out patches, shows an increase in open probability with hyperpolarization in the range of -40 to -100 mV. This channel displays a low single channel conductance of 5 pS, with subconductance states.

Depolarization-activated channels The most common type of voltage-dependent C1-

channel is activated by membrane depolarization. The relationship between channel open probability and voltage in rat hippocampal neurons is described by a Boltzmann distribution (Blatz, '91). Kinetic analysis of these channels showed that most of the observed voltage dependence was due to a decrease in the mean closed intervals with depolarization, whereas the mean open time was relatively independent of the voltage. Similar re- sults were obtained on a background C1- channel

in rat myoballs by Weiss and Magleby ('90). This study showed that the channel is activated by depolarization and that the major contribution to the increase in open probability with positive voltage was a decrease in the mean closed intervals. The only different between the C1- channel kinetics exhibited in the two preparations is in the mean open distributions, which could account for the difference in the voltage dependence of channel activation.

Polarization-inactivated channels Several large conductance C1- channels fall into

this category, being active at membrane voltages near zero and closing with depolarizing and hy- perpolarizing voltages. Gray et al. ('84) showed that, in membrane patches excised form rat cultured Schwann cells held between -10 and +20 mV, the large conductance C1- channel would remain active for long periods of time. If the membrane was polarized outside this range, the channel would close and would remain silent un- til the potential was again brought within the active range. Similar behavior was observed for the large conductance C1- channels from rat skeletal muscle (Blatz and Magleby, '83) and macrophages (Schwarze and Kolb, '84). These channels closed rapidly (within a few seconds) when the voltage was shifted (>20 mV) from zero. The rate of inac- tivation is voltage-dependent, decreasing with positive voltages. A similar behavior was reported for a 280 pS conductance C1- channel from amphibian skeletal muscle (Woll and Neumcke, '87; Woll et al., '87). In contrast to this kinetic behavior, a large conductance C1- channel found in cultured aortic endothelial cells closes at membrane potentials more negative than -40 mV (Groschner and Kukovetz, '92; Olesen and Bundgaard, '92).

These data show that the voltage sensitivity of background C1- channels is much less than that observed for voltage-gated Na' and K' channels. Additionally, the activation time constant for the hyperpolarization-activated C1- current is several hundred milliseconds, whereas the activation of Na' and K' currents occurs in fractions of seconds and milliseconds, respectively. Finally, the equivalent gating charge determined for the background C1- channels studied was always less than two, compared with an equivalent gating charge of six found for voltage-gated Na' channels.

CHANNEL PHARMACOLOGY Voltage-dependent C1- channels are blocked by

various agents that can be grouped into three cat-


egories: aromatic acids, inorganic cations, and protons. The first groups includes 9-AC, dipheny- lamine-2-carboxylate (IIPC), NPPB, and disulfonic acid stilbene derivatives including 40acetamido- 4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS), and 4,4'-diisothiocyanostilbene-2,2 '-disulfonic acid (DIDS). These compounds have been tested on different preparations and are generally found to act from the extracellular side at micromolar con- centrations. An extensive study of blockers of the C1- channel in the loop of Henle (Wangemann et al., '86) demonstrated that the channel could be blocked by both catioinic and anionic molecules with a large hydrophohic moiety and that the external channel mouth is the more susceptible site of blockade.

The molecular mechanism by which these agents block C1- channels is not known, but a shared property, hydrophobicity, suggests that hydrophobic domains on the C1- channel proteins could be the sites of action. The presence of such hydrophobic regions is consistent with the observed significant permeability of some C1- channels to aromatic compounds of smaller size (e.g., benzoate). The observation that hydrophobic NPPB reversibly blocks the outwardly rectifying C1- channel in tracheal epithelium when applied to either surface of the membrane suggests that NPPB must interact with the membrane lipid to inhibit the C1- channel (Li et al., '90). The specific- ity and potency of C1- clhannel blockers in a variety of cell types is further reviewed by Greger ('90).

Bryant and Morales-Aguilera ('7 1) demonstrated that the in vivo myotonic effects produced in mam- mals by low doses of certain aromatic monocarboxylic acids were the result of a block of C1- conductance, whereas the same aromatic monocarboxylic acids did not block C1- conductance in frog skeletal muscle in the same concentration range. This result indicates a major different in the C1- conductances of amphibian and mammalian channels. Palade and Barchi ('77b) showed that 9-AC was found to be the most potent aromatic carboxylic acid with a K, of 11 pM.

The reactive disulfonic stilbenes (DIDS and SITS) do block some voltage-dependent C1- channels, including a voltage-gated C1- conductance studied macroscopically in squid giant axon and astroglia (Inoue, '85; Gray and Ritchie, '86), the low conductance channel of Torpedo electroplax and rabbit urinary blaldder (White and Miller, '79; Hanrahan et al., '85), and the large conductance channels of cultured kidney epithelial cells, B lymphocytes, and vascular endothelial cells (Nelson

et al., '84; Bosma, '89; Groschner and Kukovetz, '92). Intracellularly or extracellularly applied DIDS reversibly blocks C1- channels in a concentration-dependent manner and independent of membrane potential (Miller and Richard, '90; Ko- kubun et al., '91; Groschner and Kukovetz, '92). The apparent reduction of the unitary current observed in the presence of DIDS is due to extremely rapid and unresolved channel flicker and suggests that this behavior is a consequence of open channel block (Kokubun et al., '91).

Inorganic cationic blockers constitute another group with a lower potency than the aromatic acids. Zn2' and Cu2+ have been found to be the most effective. In frog skeletal muscle, external Zn2+ re- duces C1- conductance (Hutter and Warner, '67; Stanfield, '70; Woodbury and Miles, '73) and has been shown to reversibly block single channel C1- currents in a voltage-dependent manner when applied to the cytoplasmic face of excised membrane patches (Woll et al., '87). In contrast, the block of macroscopic and unitary C1- currents by extracellular Zn2' has been reported to be voltage independent in skeletal muscle (Franciolini and Nonner, '87; Woll et al., '87) and bovine aortic endothelial cells (Shapiro and DeCoursey, '91; Groschner and Kukovetz, '92). The direct interac- tion of Zn2+ or H+ with the C1- channel is proposed to prevent the absorption of a cation species that promotes anion permeation and, thus, effec- tively blocks the channel (Franciolini and Nonner, '87). The K' channel blocker, tetraethylammonium ion (TEA), has been shown recently to block C1- channels of lobster walking leg nerves (Lukacs and Moczydolwski, '90) and rat cortical neurons (Sanchez and Blatz, '92). Externally applied TEA blocked fast C1- channels of rat cortical neurons in a voltage-dependent manner. The Kl was -10 mM TEA (Sanchez and Blatz, '92).

The C1- conductance of skeletal muscle is pro- foundly affected by external pH (Hutter and Warner, '67; Palade and Barchi, '77a). The voltage and pH dependence of C1- conductance in frog skeletal muscle were first described by Hutter and Warner ('72) using the three-microelectrode voltage-clamp technique. At a pH of 9.8, resting C1- conductance was about 1.8 times higher than at pH 7.4. At pH 5.0, the resting membrane conductance was about one-fifth of tha t a t pH 7.4 (Warner, '72). The effects of low pH on C1- conductance in other cell types were qualitatively similar (Shapiro and DeCoursey, '91). Protons al- ter the gating mechanism of neuronal C1- channels by decreasing Popen (Blatz, '91).

VOLTAGE-DEPENDENT CL- CHANNELS 281

CONCLUSIONS Numerous clues suggest that voltage-dependent

C1- channels are important in the control of many cellular functions. Maintaining high resting conductance and normal excitability, regulating cell volume, and modulating hormone action are some examples of the functions of these C1- channels. This diversity of function is mirrored by a similar diversity in the biophysical characteristics of the channel, such as ionic selectivity sequence, voltage dependence, unitary conductances, kinetic properties, and sensitivity to pharmacological agents. Despite the large amount of data accumulated on voltage-dependent C1- channels, identifying subsets within this class of channels with coherent biophysical features that subserve each specific function is still not possible. The lack of high affinity ligands for background C1- channels has hampered the isolation and purification of the channel protein and, thus, identification of their structure. The use of molecular genetic strategies has provided the primary structure of at least four voltage-dependent C1- channels (Jentsch et al., '90; Steinmeyer et al., '91; Thiemann et al., '92): those present in the electric organ of Torpedo, rat skeletal muscle, epithelia, and brain. At present, the molecular structure for every type of functional C1- channel has not been determined, but future identification of cloned C1- channel structures should provide a clearer understanding of the functional properties of background C1- channels.

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voltage-dependent chloride channels: invertebrates to man

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