Accessory subunits and sodium channel inactivation

subunits

Accessory

and sodium

channel

inactivation

Alan 1. Goldin University

of California,

Irvine,

USA

Recent studies have shown that the accessory subunits of the voltage-gated sodium

channel

can modify

demonstrated

that

is critical

fast

for

mechanisms sodium

the

its inactivation

cytoplasmic

inactivation.

Future

inactivation

Opinion

in Neurobiology

should

help

neurological

1993,

Functional channel

studies have Ill and

to

define

IV

the

affecting

diseases.

3:272-277

effects of accessory

proteins

on sodium

inactivation

The properties of sodium channels resulting from injection into Xenopus oocytes of RNA encoding only the ~1 subunit are not identical to those of sodium channels resulting from injection of rat brain polyadenylated RNA. In particular, the kinetics of inactivation of both rat brain type IL4 and III channels are slower, reflecting continued bursting at the single channel level [F-11] These properties are restored to normal by co-injection of low molecular weight rat brain RNA [9,10]. Similar results have been observed with the c1 subunit from the rat skeletal muscle sodium channel (&Ml, also called ~1) [ 121, The sodium channel that is found in denervated skeletal muscle (SkM2) [ 131 and rat heart (where it is called RH1) [ 141, inactivates more rapidly than the channel from rat brain when expressed in Xenopus oocytes, but still acts more slowly than the native channel from rat skeletal muscle examined in vivo.

channel accessory subunits of sodium

Other domains

for insertion of the channel into the cellular membrane. However, RNA encoding the c1 subunit alone is sufficient to encode functional channels after injection of in vitro transcribed RNA into Xenopusoocytes (for reviews of the biochemistry and molecular biology of sodium channels see [6,7,8*1>.

The voltage-gated sodium channel is responsible for the initial inward current during the depolarization phase of an action potential. The channel consists of a highly processed large subunit, termed CL,of molecular weight 23@270kDa, which in some tissues is associated with small subunits termed p. The c1 subunit comprises the actual pore of the channel. It consists of four structurally homologous domains, each containing six putative membrane-spanning a-helical regions and two putative membrane-spanning P-sheet regions, which most likely form the channel pore (Fig. 1). This structure is similar to the predicted structure of voltage-gated calcium charnels and the functional tetrameric form of voltage-gated potassium channels [ 1**I. A great deal of information has been obtained over the past few years concerning the molecular basis of sodium channel function (for recent reviews see [ 24,5*]). This review summarizes the results of studies concerning the effects of accessory the j!l subunits on sodium channel function and the importance of different structural regions of the a subunit in sodium channel inactivation.

composition

work

result in human

Introduction

Subunit

between

by which these processes occur, and how mutations channel

Current

Sodium

properties.

linker

A more extensive analysis of the gating properties of rat brain type III channels expressed in Xenopus oocytes by Moorman et al. [ 111 demonstrates that the channels gate in either a slow or a fast mode. The fast mode has fewer reopenings, a shorter mean open time and a smaller ratio of open time to pulse duration than the slow mode. The slow mode occurs in runs, and a single channel can shift between the two modes of gating. A similar analysis of rat skeletal muscle sodium channels by Zhou et al. [15-l has confirmed these two principle modes of gating (fast and slow modes), but the data also indicate that there are additional modes of gating. The data of Zhou et al shows that channels gating in the fast mode also

channels

The purified sodium channel complex from electric eel and chick heart consists of a single large c1 subunit of molecular weight 23&270 kDa. In contrast, the complex from rat tissues contains associated low molecular weight j3 subunits along with a comparable c1subunit. There are two p subunits in rat brain, p1 (36 kDa) and p2 (33 kDa), and one l3 subunit in rat muscle and heart. The 82 subunit is bound to the c1 subunit by disulfide linkage, whereas the p1 and other p subunits are noncovalently bound. In rat brain, the & subunit is necessary for functional reconstitution of the channel, while bz appears to be important

Abbreviations HYPP-hyperkalemic RHl-rat

272

heart sodium

periodic channel;

paralysis; L,,,~ Skhi-rat

linker between skeletal

@

muscle

Current

sodium

sodium

Biology

channel

channel;

domains

SkMZ-rat

Ltd ISSN 0959-4338

III and IV; PM-paramyotonia denervated

skeletal

muscle

congenita; sodium

channel.

Accessory

subunits

and sodium

channel

Coldin

inactivation

I

Iomain

Sxtracellular

ntracellular

b

-

-

NH+,

WMQ3

1484

1474

1494

I b

1504

I NFNQQ

K+&

(PMC) Dl

EQ

GQD

I

I &YN

AM&

I

1524

1514

&+KP

Q+KPlP

R+PAN+K

FQCMV

FE

(PMC) D2

D3

D4

D5

J

Fig. 1. Diagram

of the sodium channel c1 subunit showing inactivation mutations. The predicted structure of the cx subunit of the sodium channel is shown in schematic form, with the amino-acid sequence (in single-letter code) of the rat brain sodium channel L,,,_,v below. Deletions Dl, D2, D3, D4 and D5 in the rat brain IIA channel are from Patton et al. 134**1. Substitution mutations in the L,,,_,, sequence are represented by shaded regions and the position of substitution mutations in each domain is indicated by arrows. Mutation IFMQ3 in the rat brain IIA channel L,,,~,,, sequence is from West et al.[35**1. Mutations in the human skeletal muscle sodium channel gene that cause paramyotonia congenita (PMC) are changes of glycine (C) to valine W) at position 1484 and threonine (T) to methionine (M) at at position 1448 in domain IV54 position 1491 in L,,,_,” [51**1; and alterations of arginine to either cysteine or histidine CR,,,, +C/H,,,,) [52**1. Mutations in the human skeletal muscle sodium channel gene that cause hyperkalemic periodic paralysis (HYPP) are changes [531 and methionine to valine at position 1592 in domain IVS6 of threonine to methionine at position 704 in domain llS5 CT,,,, +M,,,) (M,s,,-+V,s92) [541. Abbreviations for the amino acid residues are: A (Ala); C (Cys); D (Asp); E (Clu); F (Phe); G (Cly); H (His); I (Ile); K (Lys); L (Leu); M (Met); N (Asn); P (Pro); Q (Gin); R (Arg); S (Ser); T (Thr); V Wall; and Y (Tyr).

have a shorter latency to first opening than those gating in the slow mode. Co-expression of rat skeletal muscle or brain RNA, or of RNA made in vitro from a fraction of a rat brain cDNA library, causes the channels to gate predominantly in the fast mode. These results indicate that some accessory protein(s) encoded in both rat brain and skeletal-muscle RNA modulates the activation and inactivation gating of sodium channels.

Sodium

channel

j3, subunit

It is possible that the low molecular weight factor that shifts gating modes of the sodium channels could be a p subunit. Isom et al. [16-l have recently isolated a cDNA clone encoding the rat brain p1 subunit. The predicted rat brain p1 subunit has 199 amino acids after cleavage of a 19 amino acid signal sequence at the amino terminus and has a single putative transmembrane-spanning segment 37 residues from the carboxyl terminus (Fig. 2). The protein contains four potential N-linked glycosylation sites in regions predicted to be extracellular, which is consistent with biochemical data indicating three or four N-linked carbohydrate side chains [17]. RNA hybridizing to & cDNA has been detected at high levels in rat brain and spinal cord, at moderate levels in rat heart and at low but detectable levels in rat skeletal muscle, consistent with the results from antibody-bind-

ing experiments [18]. Co-expression of RNA encoding the p1 subunit together with RNA encoding the channel IL4 CLsubunit from rat brain results in significantly faster kinetics of inactivation than those observed for the CI subunit alone. In addition, co-expression of & shifts the voltage dependence of steady-state inactivation in the negative direction and increases the level of current compared with that observed with the same quantity of cc-subunit RNA. All of these results are similar to the effects observed following co-injection of low molecular weight rat brain RNA, which suggests that the p1 subunit does modulate the inactivation properties of the sodium channel. Many different types of rat sodium channels (types IL4, III, SkMl and SkM2/RHl) demonstrate slower than normal inactivation in Xenopus oocytes, and both the IIA and SkMl channels are shifted into a faster gating mode by co-injection of rat brain RNA. However, the different rat sodium channel c1 subunits are not associated with the same p subunits in vivo. The brain sodium channel contains both p1 and p2 subunits, whereas the skeletal muscle and heart channels contain only a single p subunit, which is immunologically related to, but distinct from, the brain p1 subunit [18-201. The type III sodium channel probably represents a fetal subtype as it is expressed at highest levels during fetal and early postnatal stages of development, and the fetal channel

273

274

Signalling

mechanisms

Ltt, is 53 amino acids long (Fig. l), and its sequence is highly conserved among the different rat sodium charnels. The importance of the charged residues in LIrr-Iv has been tested in mutagenesis by Moorman et al. [33] and Patton et al. [34**]. None of the charge-neutralization mutations has profound effects on the kinetics of sodium channel inactivation, although some of the muta tions result in apparent shifts between the slow and fast gating modes. Patton et al. [34**] have also examined a series of deletions to determine if LUI_tv is essential for fast inactivation (Fig. 1). Deletion 1 completely eliminates fast inactivation, deletion 4 results in markedly slower inactivation and deletion 5 has no dramatic effect on the kinetics of fast inactivation. The complete elimination of fast inactivation by deletion 1 indicates that Ltt_tv is critical for inactivation. The fact that deletion 5 does not dramatically alter the kinetics of inactivation indicates that the effect is not simply the result of shortening the linker.

Fig. 2. Diagram of the sodium channel j3, subunit. The predicted structure of the rat brain PI subunit is shown in schematic form. The processed protein is 199 amino acids long, with one predicted transmembrane segment 37 amino acids from the carboxy1 terminus [16°*l. There are four predicted N-linked glycosylation sites in regions predicted to be extracellular. The amino terminus is thought to be extracellular on the basis of a 19 amino acid signal sequence that is not present in the mature protein.

is not associated with a mature fll subunit [18,21,22]. Despite these differences, co-expression of the rat brain & subunit modifies the inactivation properties of rat type III, SkMl and RHl channels (DE Patton, LL Isom, WA Catterall, AL Goldin, Abstract 5, Biop@ J 1993,64:A5; and JW Kyle, SY Chang, J Satin, et al., Abstract 88, Biopbys J 1993, 64:~88). Functional

importance

of a-subunit

regions for

fast inactivation Fast inactivation in the sodium channel involves some in tracellular protein component, as treatment of the inside of a squid axon with pronase markedly slows inactivation [23,24]. In the late 197Os, Armstrong and Bezanilla [25] proposed that the intracellular protein functions like a ball on a string, swinging into place to occlude the pore following activation. More recently, Hoshi et al. [26] and Zagotta et al. [27] have demonstrated that the amino terminus of the potassium channel appears to function as an inactivating particle, consistent with the model. The amino terminus of the sodium channel does not function as an inactivating particle, however, as deletion of this region does not prevent inactivation [28]. The region implicated in sodium channel inactivation is the cy toplasmic linker between domains III and IV (LII1_tv), as antibodies against LIII_tv slow inactivation [ 29,301 and coinjection of domains I-III and IV as separate constructs results in a channel that inactivates very slowly [ 281. In addition, insertions in LIII~rv [31] and phosphorylation of a single serine residue in LrlI_tv by protein kinase C slows inactivation of the channel [32].

West et al. [35*-l have tested the effects of mutations of nonpolar amino acids in LtII_rv on sodium channel inactivation. The IFMQ3 mutation (single letter codes for amino acids are used), a change of three consecutive hydrophobic residues to glutamines (Fig. l), eliminates fast inactivation in the channels. Of the three individual residues in IFMQ3, mutation M1490Q slows the kinetics of current decay threefold to fourfold, mutation 114SSQ both slows the kinetics of current decay and makes inactivation complete, and mutation F1489Q almost completely eliminates fast inactivation. These results indicate that the phenylalanine (F) at position 1489 is critical for fast sodium channel inactivation. This hydrophobic residue might stabilize the binding of the inactivating particle to its receptor on the 01subunit. Slow inactivation was intact in channels containing either the deletion 1 or IFMQ3 mutation, indicating that it does not involve this region of L,t,. This result is consistent with electrophysiological analyses demonstrating that slow inactivation is a separate voltage-dependent process [36*] that remains when fast inactivation is rem moved by bactrachotoxin [37]. Batrachotoxin appears to prevent fast inactivation by interacting with the receptor for the inactivating particle [38,39.], so that it may be a useful probe for identifying the receptor on the c1 subunit.

Clinical

effects of abnormal

sodium

channel

inactivation Disorders of sodium channel inactivation have been implicated in the etiology of a number of human neurological disorders, including hyperkalemic periodic paralysis (HYPP) [40,41], paramyotonia congenita (PMC) [40,41], atypical myotonia congenita [42*], malignant hyperthermia [43] and Guillain-Barre syndrome [44*]. With the isolation of cDNA clones encoding sodium channels from human skeletal muscle [45,46,47-l, heart [48] and brain [49], it has recently become possible to test if mutations in the sodium channel can cause these disorders. Both HYPP and PMC result from single amino acid changes in the skeletal muscle sodium channel gene (reviewed

Accessory

in [50*]). Two of the mutations that cause PMC are sin& amino acid alterations in L1ll_N; glycine to valine at position 1484 and threonine to methionine at position 1491 (Fig. 1) [51-l. Both of these changes are in the same region as the IFMQ3 mutation, further supporting the idea that this segment is critical for sodium channel inactivation. However, other mutations that cause either PMC or HYPP are located in different regions of the 01 subunit. PMC results from alteration of an arginine at position 1448 to either a cysteine or a histidine in domain Ivs4 [ 52**], and HYPP results from alteration of a threonine at position 704 to methionine in IIS 1531 or a methionine at 1592 to valine in 1vs6 [54] (Fig. 1). It is possible that these other regions may be directly involved in fast inactivation, perhaps as the receptor for the inactivating particle, or they may be important for interactions with p subunits that alter the inactivation properties of the channel.

4.

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channel

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Coldin

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42. .

43.

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Accessory

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This review summarizes

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and sodium

channel

inactivation

Coldin

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Neuron

1992, &X891-897.

Alan L Goldin, Department of Microbiology and Molecular Genetics 4025, University of California, Inine, California 92717.4025, USA

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