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Current Pharmaceutical Design, 2007, 13, 3178-3184
Multiple Modes of A-Type Potassium Current Regulation
Shi-Qing Cai, Wenchao Li and Federico Sesti*
University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Department of Physiology and Biophysics, 683 Hoes Lane, Piscataway, NJ 08854, USA
Abstract: Voltage-dependent potassium (K+) channels (Kv) regulate cell excitability by controlling the movement of K+ ions across the
membrane in response to changes in the cell voltage. The Kv family, which includes A-type channels, constitute the largest group of K+
channel genes within the superfamily of Na+, Ca 2+ and K+ voltage-gated channels. The name “A-type” stems from the typical profile of
these currents that results form the opposing effects of fast activation and inactivation. In neuronal cells, A-type currents (IA), determine
the interval between two consecutive action potentials during repetitive firing. In cardiac muscle, A-type currents (Ito), control the initial
repolarization of the myocardium. Structurally, A-type channels are tetramers of -subunits each containing six putative transmembrane
domains including a voltage-sensor. A-type channels can be modulated by means of protein-protein interactions with so-called -subunits
that control inactivation voltage sensitivity and other properties, and by post-transcriptional modifications such as phosphorylation or
oxidation. Recently a new mode of A-type regulation has been discovered in the form of a class of hybrid -subunits that posses their
own enzymatic activity. Here, we review the biophysical and physiological properties of these multiple modes of A-type channel regulation.
INTRODUCTION
A-type currents were first described in molluscan neurons by
Hagiwara and subsequently found in arthropod muscle and neuron,
and in vertebrate neurons and heart [1-3]. The name A-type derives
from the typical profile of these voltage-dependent K+ currents:
rapid activation at subthreshold voltages followed by fast inactivation. A-type channels are abundantly expressed in neurons and
cardiac and smooth muscle cells. In the nervous system, A-type
currents play a key role in the control of excitability, synaptic input,
and neurotransmitter release. In many neurons, A-type channels are
usually silent at resting membrane potentials. They however, transiently activate during the decay of the after-hyperpolarization
phase of the action potential, delaying depolarization [4]. Thus, Atype currents prolong the period between action potentials and control the neuronal firing frequency by means of inactivation. A-type
currents are present in atrial and ventricular myocytes where they
are called "transient" outward currents (Ito) and govern the initial
repolarization of the ventricular action potential [5, 6]. A-type currents exist in vascular smooth muscle cells, even though their
physiological role is not fully understood [4].
Table 1.
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The Kv Family of Voltage-Gated K + Channels
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STRUCTURE
In mammals, genes with A-type properties are found in several
sub-families of voltage-gated K+ channels, including the Kv1
(Shaker-like), Kv3 (Shaw-like) and Kv4 (Shal-like) sub-families
(Table 1). In addition, co-expression of accessory subunits with
certain Kv -subunits confers rapid inactivation to otherwise noninactivating or moderately inactivating delayed rectifier channels
[7-10]. Kv channels exhibit a predicted topology of six transmembrane spans (from S1 to S6) and a selectivity filter located between
S5 and S6. The fourth transmembrane domain, S4, provides the
location of the voltage sensor, composed of several lysine and arginine residues. Functional Kv channels are formed by four subunits packed along a central axis of symmetry, orthogonal to the
plasma membrane. The crystal structures of a bacterial and a mammalian Kv channel have been solved [11, 12]. While, the ionconduction pathway is conserved in these structures and does not
differ form that of other bacterial K+ channels such as KcsA [13],
the putative structure of the voltage-sensing domain (S1-S4) shows
*Address correspondence to this author at the University of Medicine and
Dentistry of New Jersey, Robert Wood Johnson Medical School, Department of Physiology and Biophysics, 683 Hoes Lane, Piscataway, NJ 08854,
USA; Tel: (732) 235 4032; Fax: (732) 235 5038;
E-mail: SESTIFE@UMDNJ.EDU
1381-6128/07 $50.00+.00
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a cytoplasmic location of S4 when the channel is in the closed state.
This model is presently controversial because it contradicts a large
body of earlier evidence that predicts that S4 spans the plasma
membrane.
Sub-Family
Alternative Name
Kv1.x
Shaker-like
Kv2.x
Kv3.x
Kv4.x
IA, IKUR
Shab-like
Shaw-like
IA
Shal-like
IA
Kv5.x
None
Kv6.x
Kv7.x
Current
None
KCNQ1
Kv8.x
IKs, M-current
None
Kv9.x
None
Kv10.x
eag
Kv11.x
erg
Kv12.x
elk
IKr
The family of voltage-gated K+ channel is composed of 12 sub-families. Sub-families
Kv1, Kv3 and Kv4 encode A-type channels. Kv5.x, Kv6.x, Kv8.x and Kv9.x channels
do not express measurable currents when expressed in heterologous expression systems
suggesting that these genes might encode -subunits that need to associate with other
Kv subunits to conduct currents.
N-TYPE INACTIVATION
In the late 70s, Armstrong and Bezanilla in an effort to explain
the mechanism of A-type inactivation, proposed the “ball-andchain” model, which postulated that a positively charged inactivation particle (the -ball) on a tether, prevents the movement of ions
by physically occluding the pore [14]. Using the Drosophila
channel Shaker, Zagotta, Hoshi and Aldrich, identified the location
and molecular composition of the ball. This is composed, roughly,
of the first 20 amino acids in the amino-terminal—thus the name Ntype inactivation—followed by 40 or more residues constituting the
chain [15, 16]. The inactivation ball possesses two essential
chemical characteristics: the first half is composed of hydrophobic
residues. The rest has a net positive charge which pushes the ball
toward its channel receptor site upon depolarization [17, 18]. The
© 2007 Bentham Science Publishers Ltd.
Multiple Modes of A-Type Potassium Current Regulation
details of the N-inactivation mechanism are now beginning to be
elucidated. Mackinnon and colleagues have proposed that Ninactivation occurs as a sequential reaction: the ball initially binds
to the T1 domain surface by electrostatic interactions, then it enters
through the lateral portals that connect the cytoplasm to the inner
pore, reaches the inner cavity to eventually plug the pore (Fig. 1A)
[12, 19].
Like the majority of ion-channels, A-type channels generally
contain additional regulatory proteins or -subunits that fine-tune
their properties, including trafficking, location and abundance, sensitivity to stimulation, pharmacology and gating. In the case of Atype channels, -subunits play a pivotal role in the control of inactivation, which is probably the most important physiological attribute
of these currents. Four major classes of ancillary subunits of A-type
channels have been described which differ in their sequences, structures, effects and -subunit specificity. Post-translational modifications are also pivotal in A-type K+ channel modulation. Protein
phosphorylation, for instance, represents a widespread mechanism
to regulate cellular excitability by temporarily modifying the function of K+ channels. These two fundamental modes of modulation
can co-exist in the same channel protein. These are channels containing hybrid -subunits that possess their own enzymatic activity.
Here we review the attributes of the Kv2 subunit, a soluble protein
with aldo-keto-reductase (AKR) activity [20] and of a C. elegans
KCNE-related gene, MPS-1 which exhibits kinase activity [21].
These multiple modes of channel regulation are graphically illustrated in (Figs. 1 and 2).
Current Pharmaceutical Design, 2007, Vol. 13, No. 31
brain (Kv1 and Kv2) [7], from ferret (Kv3) [24] and human
heart (hKv3) [25, 26]. Kv-subunits are soluble proteins lacking
any transmembrane domains, leader sequence or N-glycosylation
consensus sites. There are several protein kinase A (PKA) and Casein kinase 2 (CKII) consensus target sites in all Kv sequences.
The N-terminus of the Kv subunits is variable. In some isoforms
the first ± 20 residues constitute the inactivating ball (-ball) which
confers A-type characteristics to non-inactivating Kv -subunits.
Thus, Kv1 and Kv3 subunits interact with the Kv1 family of subunits and induce rapid inactivation in all Kv1 channels [7, 10,
27, 28], except Kv1.6 that has a NIP—an N-type inactivation prevention domain [29]. Kv2 has no inactivation ball therefore it does
not convert their partners into A-type channels although it can accelerate inactivation kinetics [30]. Generally, the -ball and the ball do not have direct interactions [31] although they may share
sequence homology as, for instance, the -balls of Kv1 and Kv3
with the -balls of Kv1.4 and Kv3.4. In contrast, the Kv Cterminus, which is responsible for the binding to the -subunit, is
more conserved. This domain shares sequence homology to AKR,
an enzyme that catalyzes a redox reaction using an NADPH cofactor (the reduced form of nicotinamide adenine dinucleotide phosphate). The catalytic domain is important for channel trafficking.
Thus, immunofluorescence and protein chemistry studies showed
that the expression domain alone was sufficient to increase the surface expression of Kv1.2 in heterologous expression systems [31].
It was shown that mutations in the cofactor NADP(+) binding domain, abolished the ability of several Kv isoforms to alter the trafficking of Kv1.2 [32, 33]. Intriguingly, mutations in a key catalytic
tyrosine residue found in the active site of all AKRs did not affect
trafficking characteristics. In contrast, when residues within the
NADP(+) binding pocket were mutated, they suppressed Kvmediated effects on Kv1.2 trafficking suggesting that the integrity
of the NADP(+) binding pocket, rather than catalytic activity, is
required for intracellular trafficking of Kv-Kv1 channel complexes
[32]. The structures of rat Kv2 [34] alone and in complexes
formed with the T1 domain of rat Kv1.1 [35] and with the entire rat
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ANCILLARY SUBUNITS
Kv-Subunits
Kv-subunits were originally identified in bovine rat extracts by
Parcej and colleagues [22]. Two years later, the same group isolated
cDNA encoding a -subunit co-purifying with the bovine brain
DTX acceptor complex [23]. Subsequently, cDNAs encoding three
highly related distinct -subunit isoforms were cloned from rat
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Fig. (1). N-type inactivation and its regulation by enzymes. A. Illustration of N-type K+ channel inactivation. The inactivation peptide binds to the T1 domain by electrostatic interactions and then it enters through the later openings to plug the pore. B. Enzymatic modulation of N-type inactivation. Catalytic
incorporation of negatively charged phosphates in the inactivation peptide affects its binding and/or movement by electrostatic mechanisms. C. Metabolic
modification of cysteines is associated with the formation of disulphide bridges between the inactivation peptides of -subunits or -subunits.
3180 Current Pharmaceutical Design, 2007, Vol. 13, No. 31
Kv1.2 [12] have been resolved crystallographically (Fig. 2A, B and
C). These analyses show that the Kv2-subunit binds to the T1
domain in a fourfold symmetric complex, with four T1 domains
facing the transmembrane pore and four Kv2 subunits facing the
cytoplasm. The T1 domain exhibits four prominent loops termed
contact loops that provide a large docking surface for Kv2. The T1
domain is attached to the rest of the channel by four tethers that
define four lateral openings through which K+ ions enter the channel’s pore.
K+ CHANNEL-INTERACTING PROTEINS (KCHIPS SUBUNITS)
The K+ channel interacting proteins, KChIPs, constitute an
important family of soluble auxiliary subunits of Kv4.x channels.
Four KChIPs have been identified to date, named from KChIP1 to
KChIP4. The first three members of this family, were identified by
yeast-two-hybrid screens using the N-terminus of the Kv4 channel
as bait [36]. KchIP4 was cloned later, after identification as a binding partner of presenilin 2 [37]. All four KChIP genes are highly
expressed in the brain, whereas only KChIP2 mRNA is abundant in
the heart [38]. Kv4-KchIP complexes recapitulate some gating
properties of native A-type currents in cardiac myocytes and neurons [39]. Rosati and colleagues showed a gradient of KChIP2 expression across the ventricular wall consistent with the gradient of
Ito [40]. Consistent with these data, KChIP2 knock-out mice exhibited prolonged QT interval and were susceptible to ventricular arrhythmia during electrical stimulation [41]. No description of the
potential phenotype of KChIP2 in the nervous system has been
provided however. KChIPs belong to the recoverin/NCS subfamily
of Ca2+-binding proteins and contain calcium-binding consensus
sites, composed of four EF hands each formed by two -helices
[36], in the conserved C-terminal domain. The physiological significance of these EF hands is still under investigation although
evidence suggests that hands 3 and 4 may act as calcium binders.
The KChIP subunits enhance the Kv4.2 trafficking from the endoplasmic reticulum to the plasma membrane roughly eight-fold [36,
42]. KChIP2 and 3 are targeted to the plasma membrane by palmitoylation and their plasma membrane localization is enhanced by
co-expression with Kv4.3 [43]. In contrast, KChIP1 is not palmitoylated but it is predicted to be myristoylated at its N terminus,
which contributes to the trafficking of Kv4 channels [44]. When
heterologously co-expressed, KChIPs dramatically alter the inactivation kinetics and the rate of recovery from inactivation of Kv4
channels [36]. Isoforms KchIP1 through 3 modulate Kv4 channels
in a similar fashion, and their co-expression decelerates the normally rapid rate of voltage-dependent inactivation and recovery
from inactivation [45, 46]. KchIP4, however, delays KchIP.Kv4
channel opening and it abolishes fast voltage-dependent inactivation due to a unique inactivation suppressor domain (KIS domain )
in the N-terminus which effectively converts Kv4 to a slowly inactivating delayed rectifier channel [47]. It is interesting to note that
regulatory domains such as NIP and KIS are not a prerogative of
accessory subunits. Recently we showed that a C. elegans poreforming subunit, KVS-1, possesses an N-inactivating ball preceded
by a N-Inactivation_Regulatory_Domain (NIRD) that acts to slow
down N-inactivation through steric mechanisms [48].
The structure of the KChIP1–Kv4.3 T1 complex was resolved
by the means of crystallography (Fig. 2D) [49]. It shows a crossshaped octamer having the T1 tetramer at the center and individual
KChIPs extending radially. Ten KChIP1 -helices form a clamshell-like structure organized in four hands each composed by two
helices. The tenth helix, H10, anchors the KChIP1 subunit to the
channel by interacting with its N-terminus. There are two principal
interaction sites. A Kv4 channel N-terminal hydrophobic segment
interacts with the KChIP1 H10 helix. The second point of contact
occurs at the level of a T1 assembly domain loop and the H2 helix
of KChIP1. Functional and biochemical studies indicate that the
first site controls channel trafficking, whereas the second affects
Cai et al.
channel gating. These data are consistent with previous crystallographic studies of complexes formed by KChIP1 and partial Kv4
N-terminus domains [50, 51]. Moreover, the T1 docking loop provides specificity of interaction with Kv4 channels. When this domain was inserted into the Kv1.2 N terminus, KChIP1 could assemble with this mutant channel [51]. The stoichiometry of Kv4.2KChIP2 channel complex was determined by Kim and colleagues
as 1 to 1 ratio [52]. Using electron microscopy, the same group
visualized the Kv4.2-KchIP2 channel complex at 21 Å resolution
[53]. Four KChIP2 subunits fit into four peripheral columns that
extend from the membrane embedded portion of Kv4.2.
KCNE ANCILLARY SUBUNITS
KCNE genes encode integral membrane proteins that function
as ancillary subunits of Kv channels. KCNE genes are found in
invertebrates (C. elegans), amphibians (Xenopus laevis) and mammals, including homo sapiens [8, 9, 54, 55]. KCNE proteins range
from approx 10-30 kDa and have a single transmembrane span
which is the most conserved domain in these proteins. KCNE proteins have been shown to modulate mammalian A-type currents.
Thus, KCNE2, which is expressed in human left ventricle assembles with Kv4.2 in heterologous expression systems suggesting that
KCNE2 might be a component of Ito native channels [56]. In addition, KCNE subunits can interact with non-inactivating or moderately inactivating Kv channels which however can be converted
into A-type channels by KCNE and/or Kv subunits [57-61]. The
importance of KCNE genes in regulating A-type currents is emphasized in C. elegans. Four KCNE-related genes, termed mps, operate
in the nervous system of the animal [8, 9]. MPS proteins have been
shown to interact with a moderately inactivating potassium channel,
KVS-1, in vitro and in vivo. When expressed in heterologous expression systems each MPS protein acts to alter KVS-1 attributes.
MPS-1 and MPS-4 convert KVS-1 into an A-type channel. In contrast, MPS-3 suppresses KVS-1 inactivation. It is interesting to note
that MPS proteins are a means to generate heterogeneity of Kv
currents in the same neuron. In the chemosensory ADF neurons,
MPS-1, MPS-2 and MPS-3 combine with KVS-1 to form two distinct channel complexes: binary complexes containing only MPS-1
subunits (MPS-1-KVS-1) and ternary complexes containing MPS2, MPS-3 and KVS-1. These complexes appear to control specific
neuronal functions. The MPS-2-MPS-3-KVS-1 ternary complex in
particular, is required to fine tune the taste of the animal for sodium
ions. [8]. The role of the MPS-1-KVS-1 complex in ADF neurons is
more elusive. This protein is expressed in several other chemosensory neurons therefore its destabilization does not impact a single
neuron type but rather causes multiple sensory defects [9].
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DIPEPTIDYL PEPTIDASE-LIKE PROTEINS
The fourth class of ancillary subunits of A-type channels discussed in this review is represented by the peptidase-like proteins.
The name of these subunits stems form their sequence homology to
the peptidyl aminoprotease CD26/DPP4 [62]. Despite this similarity, they lack enzymatic activity, due to a S to D substitution in the
DDH catalytic triad [63]. DPP6 was originally identified by copurification with Kv4.2 from rat brain membranes [62]. DPP6 facilitates trafficking and membrane targeting, accelerates inactivation
kinetics, alters the voltage dependence of activation and inactivation and accelerates recovery from inactivation thereby conferring
ISA-like properties to the current. At present two DPP-like subunits,
DPP6 and DPP10, have been shown to be essential components of
Kv4 and Kv1 potassium channels [62, 64, 65]. Structurally, DPP
subunits have a single transmembrane domain a short N-terminus
and a large C-terminus containing the aminopeptidase-like domain.
The protein is oriented in the membrane with the N-terminus in the
cytoplasm. The crystal structure of the amino-peptidase-like site of
DPP6 (extracellular domain) has been solved at 3 Å resolution (Fig.
2E) [63]. It is a dimer formed by two identical monomers. Each
monomer is composed by a eight-bladed -propeller and a / hy-
Multiple Modes of A-Type Potassium Current Regulation
Current Pharmaceutical Design, 2007, Vol. 13, No. 31
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Fig. (2). Experimental structures of -subunts.
A. Crystal structure of Kv2 (amino acids 36 to 367) at 2.8 Å resolution. The AKR domain is depicted in turquoise. Adapted from [34].
B. Surface representation of the Kv1.2-Kv2 complex at 2.9 Å resolution. Basic and acidic residues are depicted, respectively in blue and red colors. The
membrane spanning portion of the channel, (TM], the T1 domain and Kv2, (), are indicated. Adapted from [12].
C. Hypothetical model for the binding of the -ball to the channel. An inactivation peptide corresponding to the 22 N-terminal residues of Kv1 was modeled
in an extended conformation to enter a side portal and plug the inner pore of the channel. Adapted from [12].
D. Model of the Kv4.3–KChIP complex based on the Kv1.2 structure. KChIP1 (cyan), Kv4.3 T1 domain (orange) and the transmembrane domains (TM, dark
red) are indicated. Adapted from [49].
E. Crystal structure the extracellular domain of the DPP6 dimer at 3.0 Å resolution. The color changes from blue (N terminus) to red (C terminus). Carbohydrates with glycosylation sites are shown in ball-and-stick representation and the “catalytic triad” is shown in CPK representation. Adapted from [63].
drolase domain. The dimer interface is formed by the last -strand
of the propeller domain and two helices of the / hydrolase and by
the -hairpin insertion motif of the -propeller domain. The active
site is located at the interface of the / domain and the propeller.
DPP subunits exhibit a slightly higher abundance of histidine residues than average suggesting that they might have a role in regulating channels’ susceptibility to extracellular pH.
POST-TRANSCRIPTIONAL MODIFICATIONS
A large body of evidence supports the notion that A-type K+
currents in both neuronal and cardiac cells can be modulated by
phosphorylation [21, 39, 66-68]. Often, phosphorylation of these
channels results in altered N-type inactivation. This is not surprising if one considers the key role of electrostatic charge in the
mechanisms underlying N-type inactivation as well the physiological role of this feature (Fig. 1B). Thus, phosphorylation of serine
residues in the -ball in Kv3.4 abolished N-inactivation [67]. Structural analysis by NMR indicated that this mechanism stems from a
structural rearrangement of the ball which distinctly alters inactivation kinetics [66]. Phosphorylation of a tyrosine in the inactivation
ball of the Shaker channel [69], and phosphorylation of the Nterminus of Kv1.3 [70] also removed the fast inactivation of these
currents. Kv4.x channels have been reported to be phosphorylated
by PKA [71], PKC [72], MAPK [73-75] and SGK [76] in vivo and
in vitro. Activation by PKC suppresses Kv4.2 or Kv4.3 current in
Xenopus oocytes and PKA suppresses Kv4.2 current in hippocampal neurons; on the contrary, co-expression with SGK1 increases
Kv4.3 channel current in heterologous expression systems. Phosphorylation does not always induce detectable functional modifications. For instance, two PKA sites and three ERK/MAPK phosphorylation sites [73] in Kv4.2 are phosphorylated in vivo [71].
However, PKA phosphorylation of only one site—serine-552—has
been found to affect channel’s function: it shifts the voltage dependence of activation of the channel [75]. Some protein kinases
such as ERK/MAPK act to regulate their channel targets directly
[74]. Other kinases need anchor proteins to assist them to modulate
potassium channel currents. Schradder and colleagues found that
PKA regulation of Kv4.2 currents required the presence of a KChIP
subunit [75]. Despite the ability of PKA to phosphorylate the Kv4.2
-subunit in the absence of KChIP3, PKA was unable to alter the
3182 Current Pharmaceutical Design, 2007, Vol. 13, No. 31
biophysical properties of the channel by this mechanism alone.
These findings reveal an unexpected complexity to the structurefunction relationships for kinase regulation of membrane potassium
channels.
A variety of agents normally present in biological cells can
oxidize A-type channels leading to removal or introduction of Ntype inactivation. Thus, a cloned mammalian A type potassium
channel, RCK, lost its N-type component of inactivation after oxidation of a cysteine and consequent formation of disulphide bridges
in the inactivation ball domain (Fig. 1C) [77]. On the other side of
the spectrum, oxidation of histidines and cysteines in the Nterminus of mouse Kv1.7 induced fast inactivation, whereas reducing conditions reversed this effect [78]. The same phenomenon was
observed in the potassium channels Kv1.4, Kv3.4 and that associate
with Kv subunits that also have a conserved cysteine in the -ball
[79, 80]. Oxidation of residues other than cysteines has also been
shown to affect N-type inactivation. Conversion of methionine into
methionine sulfoxide in the inactivation ball of the ShC/ShB channel, suppressed N-type inactivation [81, 82]. Unlike cysteine, oxidation of methionine cannot be reversed by reducing agents and in
these cases enzymes such as the peptide methionine sulfoxide reductase mediate the reversibility of these reactions. It is not clear
whether oxidation of methionine is a common mechanism underlying potassium channel regulation. For example, oxidation of methionine in the N-terminus of mouse KV1.7 did not affect Ninactivation [78].
In addition to phosphorylation and oxidation other common
post-transcriptional modifications such as N-glycosylation and
palmitoylation have been shown to influence A-type function, but
little is known about the impact of these mechanisms on native Atype channels [43, 83]. Finally, Oliver and others showed that
phospholipids can control A-type inactivation in vitro [84]. Thus,
phosphoinositides can bind the -ball of Kv1.1 and Kv3.4 removing
N-type inactivation whereas arachidonic acid induces N-inactivation in Kv3.1. Given the second messenger role of PIP2, these findings may underscore a new mode of enzymatic modulation—by
phospholipases—of A-type currents.
Cai et al.
elements that can act directly to alter their own function. This leads
us to speculate that Kv and MPS-1 may provide examples of novel
mechanisms of dynamic regulation of electrical signaling in the
nervous system. Further studies will address these fundamental
questions.
FUTURE DIRECTIONS AND THE C. ELEGANS MODEL
Even though it is well known that the regulation of A-type potassium channels by protein-protein interactions or posttranslational modifications are critical for life processes, the big
challenge is to determine where and when these regulations occur
in vivo. Invertebrate animal models such as C. elegans can significantly contribute to this effort. All major families of K+ channel
genes are represented in C. elegans [85]. To date, two Kv channels
in C. elegans have been shown to produce A-type currents [9, 86]
and a sub-family of KCNE genes was recently identified [8, 9]. The
possibility to perform genetic manipulations and to assess the effect
of these manipulations in vivo along with new techniques that have
remarkably advanced the ability to electrophysiologically record K +
currents in native cells [87] make C. elegans an unprecedented tool
for the study of the A-type K+ channels. C. elegans seems a reasonable system to overcome the limitation of higher organisms without
losing the ability to work in true physiological context.
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ENZYMATIC MODULATION OF A-TYPE CURRENTS BY
-SUBUNITS
Recent observations indicate that the two fundamental modes of
A-type K+ channel regulation—assembly with -subunits and enzymatic modulation—can co-exist in the same protein [20, 21], as
bifunctional -subunits which posses enzymatic activity. We mentioned before that the C-terminus of the Kv subunits shares sequence homology to AKR. The role of the putative catalytic activity
of Kv, as well its biological function, has been a mystery for a
long time, until recently it was demonstrated that Kv2 possesses
AKR activity that controls inactivation kinetics [20]. Using KV1.4
as substrate, Weng and colleagues showed that Kv2 modulates
Kv1.4 channel inactivation through oxidizing the bound NADPH
cofactor. Since the subunit can assemble with a series of poreforming subunits in different tissues, the finding may provide a link
between modulation of potassium channels and the redox state in
vivo. The second example is represented by the C. elegans KCNErelated gene, MPS-1 [21]. Nine characteristic protein kinase catalytic subdomains can be recognized in the C-terminus of MPS-1
(Shi-Qing Cai unpublished observations). Recombinant MPS-1 was
shown to catalyze incorporation of 32P into myelin basic protein (a
standard S/T kinase substrate) and more importantly, MPS-1 was
found to phosphorylate one of its physiological substrates the KVS1 K+ channel. As with Kv subunits, MPS-1 also acts to modulate
KVS-1 function through independent mechanisms: the kinase activity decreases the steady-state open probability of the complex, resulting in reduced macroscopic current, whereas its -subunit nature confers A-type characteristics. These bifunctional -subunits
convert their K+ channel partners from passive elements into active
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ACKNOWLEDGEMENTS
We are deeply indebted to Dr. John Lenard for critical reading
of the manuscript. This work was supported by an NIH grant
(R01GM68581) to FS.
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