Amino Acid Transport Across the Blood—Brain Barrier

C H A P T E R

Amino Acid Transport Across the Blood—Brain Barrier QUENTIN R. SMITH, HARITHA MANDULA, AND JAGAN M. R. PAREPALLY

disease and by the neuronal degeneration and death that occurs with excessive excitotoxic amino acid release in hypoxia, hypoglycemia, ischemia, and seizures. Brain amino acid pools are insulated from changes in plasma due in part to the presence of the bloodbrain barrier (BBB). The BBB is a system of tissue sites including brain vascular endothelial cells, choroid plexus epithelial cells and arachnoid membrane, which together restrict and regulate the exchange of polar solutes between plasma and brain extracellular fluid [28]. The physical barrier at each site is formed by a single layer of cells joined together by multiple bands of tight junctions [17]. These junctions essentially seal adjacent cells together and block the aqueous paracellular diffusion pathway. In the absence of paracellular diffusion, polar solutes, such as amino acids, are forced to cross the BBB either by passive diffusion through lipoid BBB membranes or by carrier-mediated transport across the membranes via one of more than 12 BBB amino acid transport proteins. Only approximately half of the 20 amino acids that are required for brain development and function can be synthesized within the central nervous system (CNS). This includes both the small neutral and anionic amino acids that serve as neurotransmitters or neuromodulators. The remaining large neutral and cationic amino acids are nutritionally essential and must be supplied ultimately from the diet via gastrointestinal absorption and transport across the BBB. In the past 12 years, marked advances have been made in the identification and characterization of the specific transport proteins that mediate amino acid flux across the BBB and within the CNS. This chapter summarizes the current knowledge of the BBB amino acid transporters and how they function to regulate brain extracellular fluid amino acid concentrations. The primary focus is on the transporters of the brain

ABSTRACT Amino acids serve multiple roles in brain as neurotransmitters, neurotransmitter precursors, and building blocks of peptides and proteins. Their levels in brain are closely regulated in part by controlled transport across the blood-brain barrier (BBB). The BBB is located primarily at the brain capillary endothelium, which restricts and regulates the flux rates of 20 or more amino acids between the plasma and brain interstitial fluid. This regulation is achieved in good part through the selective action of 12 or more amino acid transporter proteins, which are highly expressed at the BBB and function predominantly to shuttle amino acids into or out of brain. This review summarizes the current knowledge of these BBB amino acid transport systems and their impact on brain metabolism and function.

BRAIN AMINO ACID REGULATION The brain depends on a diverse array of amino acids for normal development and function. Over 20 are required to sustain cerebral protein and peptide synthesis. Four (glutamate, aspartate, glycine, and GABA) serve as neurotransmitters, three (tryptophan, histidine, and tyrosine) as neurotransmitter precursors, and two thyronine derivatives (T3 and T4) as hormones. Further, an additional 20 perform critical roles as neuromodulators, intermediary metabolites, and essential precursors for other pathways (e.g., creatine, palanine, taurine, quinolinic acid, and kynurenic acid). Most must be tightly regulated within brain neuronal, astrocytic, extracellular, and synaptic compartments. Imbalances profoundly influence brain function, as shown by the irreversible mental retardation that occurs in phenylketonuria and maple syrup urine Handbook of Biologically Active Peptides

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capillary endothelium, which is thought to be the principal site of exchange for most solutes between brain interstitial fluid and the circulation. BLOOD-BRAIN BARRIER AMINO ACID TRANSPORT Figure 1 illustrates the amino acid transporters of the BBB. Separate mechanisms have been identified for large neutral amino acids (System L and LNAA), small neutral amino acids (Systems A and ASC), cationic amino acids (System y"^), anionic amino acids (System X"), P-amino acids (System P), creatine, and thyroid hormones. Transport is either active (against the electrochemical gradient and energized by linkage to ion movement) or passive (flowing down the electrochemical gradient without a requirement for additional energy). Some carriers are located at both the capillary luminal and abluminal membranes and mediate rapid bidirectional exchange across the BBB (e.g., Systems L and y^), whereas others (e.g.. System A and LNAA) are located only at the capillary abluminal membrane and appear to mediate primarily active amino acid efflux from the CNS. The properties of the individual carriers are summarized in Table 1.

Phe, Trp Leu, Met lie, Tyr His, Thr Val, Gin BCH

Arg Lys Orn

Ala Ser Pro Gin Asn His MeAlB

Most BBB amino acid transport carriers have been shown to follow Michaelis-Menten transport kinetics [27, 41-42]. Unidirectional influx rates for amino acid uptake from plasma can be estimated with the Michaelis-Menten equation adapted for multiple substrate competition as Influx = {V^C)I[K^

{\ + UC^lK^i))

+ C]

where C = plasma concentration of the amino acid of interest, Knax (maximal transport velocity) and ^ (half saturation concentration) are the transport constants of the amino acid, and Q and K^^i are the plasma concentration and corresponding half saturation constant of each competing amino acid.

TRANSPORT SYSTEMS System y"^/Cationic Amino Acid Transporter System yVcationic amino acid transporter (CAT)l was the first amino acid transport protein identified molecularly at the BBB. It mediates the brain uptake of three cationic amino acids: L-arginine, L-lysine, and Lornithine. The cDNA for CATl was cloned serendipi-

Brain Side Ala Ser Cys Met Val

M/m /ASCTV

V 2 /(

Gin Asn His

Glu Asp

(1)

Leu, lie Val, Trp Taurine Tyr, Phe Met, Ala GABA Hypotaurine His, BCH Betaine p-Alanine

T4

rT,

Weak T4

T.

V/EAAT\/LNAAV ^ /\ 1,2,3;

Ala, Ser Cys,Thr during development

Blood Side FIGURE 1 , Diagram of amino acid transport systems at the brain capillary endothelium and their localization to the capillary luminal (blood-facing) or abluminal (brain-facing) membranes. Shaded systems are Na^-dependent (two arrows) or Na^- and Cr-dependent (three arrows). Unshaded systems are sodium independent. Amino acid assignments are from [27, 30-34, 41-42].

AMINO ACID TRANSPORT ACROSS THE BLOOD—BRAIN BARRIER

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TABLE 1. Brain Capillary Amino Acid Transport Systems. Transport System

Gene Protein

Ion Dependence

Localization

System L

LAT1/SLC7A5

Neutral amino acid Both

System A

ATA2/SLC38A2

Abluminal

Na

System ASC System N System LNAA

ASCT2/SLC1A5

Abluminal Abluminal Abluminal

Na Na Na

System y"^

CAT1/SLC7A1

System X" System ASC

EAAT1-3/SLC1A1-3 ASCT2/SLC1A5

P-Amino acid GABA Creatine Oatp2

TAUT/SLC6A6 GAT2/SLC6A13 CRT/SLC6A8 Old—Oatp2/SLC21A5 New—Oatp1 a4/SLC01 A4 Old—Oatp14/SLC21A4 New—Oatp1 a4/SLC01 A4

Oatp14

Basic amino acid Both Acidic amino acid Luminal Abluminal Miscellaneous systems Abluminal Abluminal Luminal Both Present, but not localized to membrane

tously by Albritton et aL [3] in 1989 and subsequently shown independently by Kim et al. [22] and Wang et al. [54] to mediate high-affinity cationic amino acid transport. Stoll et al. [42] in 1993 demonstrated high levels of G\T1 mRNA in brain capillaries. The CATl protein was later shown to be present at both the brain capillary luminal and abluminal membranes [46]. CATl (SLC7A1) is a member of a family of cationic amino acid transporters (CAT 1-4) [16, 53]. Human CATl is a 629-amino-acid glycoprotein with 12-14 transmembrane-spanning regions [2]. The kinetic properties and substrate specificity of in vivo BBB cationic amino acid uptake match that of the cloned CATl transporter protein with K^ values for L-arginine, L-lysine, and L-ornithine of between 50 and 120|LIM. BBB CATl transport is Na^ independent and facilitated, mediating bidirectional exchange across both the capillary luminal and abluminal membranes. Table 2 summarizes plasma concentrations and BBB Michaelis-Menten kinetic constants for amino acids that are transported into brain. Because of the presence of System y^/CATl at the BBB, essential cationic amino acids, including L-lysine and -arginine, are taken up and equilibrate in brain with a half-life of <15min. However, due to the high affinity of CATl, it is essentially saturated with cationic amino acids as a group at normal

Representative Amino Acid Substrates Phe, Trp, Leu, Met, lie Tyr, His, Thr, Val, Gin BCH Ala, Ser, Pro, Gin, Asn His, MeAlB Ala, Cys, Ser, Met, Val Gin, Asn, His Leu, lie, Val, Trp, Tyr Phe, Met, Ala, His, BCH Arg, Lys, Orn

~ Na Na

Glu, Asp L-Asp

Na, CI Na, CI Na, CI

Taurine, p-alanine GABA, Betaine Creatine Weak—T3, T4

—

T4, rT3 (Weak T3)

plasma concentrations. The saturation percentage can be calculated by the formula: Saturation (%) = 100 x MC/K^ )/[l +

I.(C/K^)]

With this, BBB CATl is predicted to be >85% saturated with cationic amino acid substrates at normal plasma concentrations. As a consequence, total cationic amino acid influx is predicted to remain fairly stable (within -twofold), with fluctuations in plasma concentration. However, the transport rates for individual cationic amino acids can change if plasma concentrations vary so as to significantly modify the fractional occupation of transporter binding sites by the amino acid. Such has been shown to occur following administration of a single cationic amino acid [6]. With transport saturation, the selective elevation in the plasma concentration of one cationic amino acid reduces the BBB influx of other amino acids sharing the same carrier by competitive inhibition. The presence of CATl at the BBB allows for the rapid bidirectional exchange of nutritionally essential cationic amino acids between plasma and brain interstitial fluid to support brain protein and peptide synthesis as well as nitric oxide generation. A CATl knockout mouse model has been developed that

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TABLE 2. Blood-Brain Barrier Transport Constants for Brain Uptake of Neutral Annino Acids, Basic Amino Acids, Acidic Amino Acids, and Thyroid Hormones. Amino Acid

Plasma Concentration (^iM)

PHE TRP LEU MET ILE TYR HIS VAL THR GLN

81 82 175 64 87 63 95 181 237 485

ARG LYS ORN

117 245 98

GLU ASP T3

Km (^tM)

Knax

(nmol/min/g)

Kn(app) (^M)

Neutral amino acids (System L1) 11 41 170 15 35 330 29 59 500 40 25 860 56 60 1210 64 96 1420 100 2220 61 210 49 4690 17 220 4860 880 43 19900 Basic amino acids (System /) 56 24 70 22 109 26

302 279 718

Influx (nmol/min/g) 13.2 8.2^ 14.5 1.7 4.0 4.1 2.5 1.8 0.8 1.0 6.7 10.3 3.1

Acidic amino acids (System X~) 24 0.21 101 0.13 Ttiyroid hormones 0.26 0.16

^As measured by the in situ rat brain perfusion technique. Values are taken from [27, 41,42]. ^Estimated assuming -70% of albumin-bound TRP contributes to brain uptake. V^ax is the maximal saturable transport capacity. Km is the half-saturation concentration in the absence of competitors, /
produces homozygous pups that die at birth [36]. The results suggest that CATl is critical for cellular cationic amino acid uptake and regulation. System L/Large Neutral Amino Acid Transporter 1 System L/large neutral amino acid transporter (LAT) 1, like CATl, mediates the bidirectional exchange of essential amino acids across the BBB. System L was first described by Oxender and Christensen [35] and was subsequently shown to facilitate BBB uptake of more than eight large neutral amino acids, including L-phenylalanine, L-tryptotophan, L-leucine, L-methionine, L-tyrosine, L-isoleucine, L-histidine (neutral), Lvaline, and threonine [27, 30-31, 38-39, 41]. The transporter is Na^- and H^-independent, and has traditionally been defined by sensitivity to 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH). However, sub-

sequent work has demonstrated that BCH can interact with other transport proteins (e.g., B^^^ and LNAA). The gene for the System L/LATl carrier was cloned in 1995 and shown by Kanai et al. [20] to encode for a ~41-kDa light-chain protein (LATl) that mediates Naindependent, BCH-sensitive, large neutral amino acid transport. The substrate affinity and selectivity of the cloned transporter [20] match well those reported for System L transport at the BBB [41]. LATl mRNA is highly expressed at the BBB, and the LATl protein has been shown to be present at both the luminal and abluminal membranes of brain capillaries [11, 18]. LATl was the first member (SLC7A5) discovered of a large family of heteromeric amino acid transporters consisting of different light and heavy chains [5, 9-10]. LATl has 12 predicted transmembrane-spanning regions and is found in cells linked via a disulfide bond to a heavy chain subunit (4F2/CD98). Other members of the LAT family (LAT2-4) are present in brain, but

AMINO ACID TRANSPORT ACROSS THE BLOOD-BRAIN BARRIER

distinct roles for these transporters have not been established at the B B B . Like CATl, BBB LATl is heavily (>95%) saturated with amino acid substrates as a group at normal plasma concentrations and exhibits potent amino acid competition effects. Selective elevation of the plasma concentration of a single large neutral amino acid dramatically reduces brain influx rates of competing amino acids. Such has been shown to occur in phenylketonuria. Dietary supplementation with large neutral amino acids can partially overcome this inhibition and reduce brain phenylalanine to levels closer to normal [26].

System N L-Glutamine and asparagine were initially proposed to be taken up into brain by System L based on crossinhibition with L-phenylalanine in saline [31]. Consistent with this, the K^ values for L-glutamine and L-asparagine (1.6 and 2.1 mM) with cloned LATl expressed in Xenopus oocyi^s [55] match those reported for the BBB L System (0.9 and 3.8 mM) in the absence of competitors [41]. However, in plasma. System L is more than 95% saturated with neutral amino acids as a group, and thus the flux rate for a given amino acid is only a small fraction of that from competitor-free saline. By the use of the reported BBB System L transport K^ax and X,„ values of Smith et al. [41], a unidirectional brain influx rate for L-glutamine of 15.3nmol/min/g is predicted at 485 |lM in competitor-free saline. In contrast, with rat serum, the predicted influx rate is only LOnmol/min/g (6.5%). Using artificial blood perfusate with balanced amino acids, Ennisetal. [12] obtained a unidirectional brain influx rate for L-glutamine of 4.9nmol/min/g, of which, from the calculation, the BBB L System is expected to contribute less than 20%. They found that the majority of BBB L-glutamine uptake was mediated by a Na^-dependent mechanism with properties similar to System N of the liver. Lee et al. [25] and O'Kane et al. [33] confirmed presence of System N activity at the BBB using isolated bovine brain endothelial cell membranes. However, in their preparation, they found Na^-dependent glutamine transport only at the capillary abluminal membrane and of this, 80% was mediated by System N and the remainder by System A. It was suggested that active BBB System N transport serves the brain by removing excess glutamine from brain and thereby contributing to the brain nitrogen metabolism and homeostasis [25].

System A/ATA2 Small neutral amino acids, including L-alanine, glycine, and proline, show very limited uptake into the brain and instead are effluxed from brain via the active

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transport by one or more Na^-dependent transport systems. The first such mechanism to be demonstrated at the BBB was System A (ATA), which is localized solely to the BBB capillary abluminal membrane [8, 34, 3 8 39]. System A mediates Na^-dependent transport of Lalanine, L-serine, L-proline, L-asparagine, and L-glutamine [8, 34]. A/-methylaminoisobutyric acid (MeAIB) is a selective System A substrate. Of the family of System A transporters (ATAl-3), the ATA2 isoform (SLC38A2) is predominantly expressed at the BBB [45]. System A is proposed to aid in the homeostasis of brain amino acids by clearing small neutral amino acids from brain extracellular fluid. Together with other Na-dependent transporters, it helps maintain brain extracellular fluid amino acid concentrations at one-tenth the levels in plasma [34, 45].

System ASC/ASCTl and -2 System ASC is an additional Na-dependent, small neutral amino acid carrier that has been demonstrated to be present at brain capillary endothelial cell membranes. It expresses affinity for L-alanine, L-serine, Lcysteine, L-methionine, L-glycine, L-threonine, and, to a lesser extent, L-valine, L-isoleucine, and L-leucine [34]. It can be distinguished from System A because it shows no activity towards MeAIB. Tayarani et al. [49] first noted this component using isolated rat cerebral microvessels and attributed it to System ASC, due to its preference for the small neutral amino acids alanine, serine, and cysteine. In adult animals. System ASC is localized almost exclusively to the capillary abluminal membrane and is mediated by the ASCT2 isoform (SLC1A5), which has a critical role in effluxing small neutral amino acids from brain [50]. In developing animals, ASCTl (SLC1A4) is also transiently expressed at the BBB at both the capillary luminal and abluminal membranes and may have a role in delivering small neutral amino acids to the growing brain [37].

System B^ or LNAA In addition to the Na^-dependent small neutral amino acid transporters localized at the brain capillary abluminal membrane, Hawkins' group has proposed that a Na^-dependent large neutral amino acid transporter is also present at the capillary abluminal membrane that contributes to large neutral amino acid efflux across the BBB [32, 34, 39]. This transporter was initially identified as System B^^, but eventually this designation was changed because of the lack of crossinhibition between basic and neutral amino acids. A similar reasoning excluded System y^L. The Na^-dependent component of large neutral amino acid transport at the capillary abluminal membrane was found to be

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BCH-sensitive, high affinity {K^ = 21 |LlM for L-leucine), and active for most all the substrates that are transported by the Na^-independent BBB System L. System X / E A A T 1-3 Anionic amino acids (i.e., glutamate and aspartate) are taken up into the brain and brain microvessels at low rates by a sodium-dependent, high-affinity, lowcapacity system tentatively identified as System X~ {K^ = 1.9 |lM for L-glutamate) [4, 31]. Because these amino acids are neuroexcitatory and toxic at high concentrations, influx from blood must be tightly limited. Thus, the transport capacity is a small fraction (<1/100) of that for large neutral and basic amino acids. Brain regulation of acidic amino acids is also obtained by a highlevel expression of sodium-dependent excitatory amino acid transporters—EAATl, -2, and -3 (SLClAl-3)—at the BBB abluminal membrane, which actively efflux anionic amino acids across the BBB to the circulation [33]. The L-glutamate K^ for abluminal membrane uptake is 14|lM, with a maximal transport capacity similar to that reported for System L [33, 39]. In addition, Tetsuka et al. [50] also demonstrated that ASCT2 contributes to L-aspartic acid efflux from brain. Together, these systems form a potent barrier to excitatory amino acid neurotoxicity from the circulation. System TAUT Taurine, hypotaurine, (J-alanine, and other p-amino acids are slowly taken up into brain at the BBB by a high-affinity, low-capacity, Na^- and Cr-dependent transporter [7, 23, 47, 48]. This transporter mediates active uptake into the brain [47] of P-amino acids with Xm values of 10-50|LlM. Taurine transport at the BBB has been shown to be mediated by the TauT transporter (SLC6A6), which is a 620-amino-acid protein with a molecular weight of 70kDa and 12 predicted transmembrane-spanning regions [21, 52]. This transporter appears to be expressed on both the capillary luminal and abluminal membranes for active uptake and efflux from the CNS [24]. System CRT Creatine is actively taken up into brain at the BBB by the Na- and Cl-dependent CRT transporter (SLC6A8) and can be inhibited by P-guanidinopropionate and guanidoacetate [29]. System Betaine-GABA/GAT2 GABA is actively effluxed from brain at the BBB by the Na^- and Cl'-dependent GABA-Betaine transporter

(GAT2, SLC6A13) [19, 44]. The Kn is 680 ^iM with dense expression at the capillary abluminal membrane. The GAT2 transporter differs from that in neurons and glia (GATl and -3) and has been shown to have a significant role in removal of GABA from the brain extracellular fluid. Betaine, P-alanine, taurine, and quinidine all inhibited GABA uptake at the BBB by this system [44]. Thyroid Hormones The biologically active thyroid hormones triiodothyronine (T3) and thyroxine (T4) are lipophilic L-amino acids that taken up into brain across the BBB by saturable transport. Over 10 different gene products have been discovered that mediate saturable thyroid hormone transport [15]. The first was LATl, which has been shown to mediate L-T3, and to a lesser extent L-T4, transport across biological membranes. LATl thyroid hormone transport is sensitive to competitive inhibition by the L-system selective substrate BCH but not by triiodothyroacetic acid [13]. This, however, does not match in vivo BBB L-T3 uptake, which is blocked by lOjLlM triiodothyroacetic acid but not by 1 mM BCH, suggesting that in vivo the bulk of BBB T3 transport is mediated by a separate carrier. Consistent with this, LATl is predicted to contribute less than 15% of measured BBB T3 flux based on the expressed LATl T3/phenylalanine transport ratio of Friesema et al. [13] and the in vivo BBB phenylalanine transport rate [27, 41]. Alternate BBB transport carriers that have been shown to mediate thyroid-hormone transport and to be expressed at some site of the BBB include organic anion transporter protein (Oatp)2 and Oatpl4 at the brain capillaries and MCT8 at the choroid plexus [1, 14, 43, 51]. Oatpl4 transports T4 preferentially over T3 [43]. Monocarboxylic acid transporter (MCT)8 is highly expressed at the choroid plexus and the circumventricular organs [14]. Final demonstration of the mechanism that mediates brain T3 uptake awaits additional experiments.

CONCLUSION Over the past 15 years, significant progress has been made in the identification and characterization of molecular transport systems that mediate amino acid transport across the BBB. The genes and proteins of at least 12 BBB amino acid transporters have been identified. Work is under way to identif)^ additional transporters and to resolve the contributions of transporters that have already been identified. The current results have documented the marked polarization of BBB amino acid transport processes, with passive facilitated carriers (LATl and CATl) localized on the capillary luminal

AMINO ACID TRANSPORT ACROSS THE BLOOD-BRAIN BARRIER

membrane and most Na-dependent active transporters (ATA2, ASCT2, System N, System LNAA, EAATl-3, TAUT, and GAT2) localized on the capillary abluminal membrane for active efflux from brain. Future work will address more closely how these systems work as a unit to regulate brain amino acid concentrations in health and disease. These BBB amino acid transporters also offer a valuable doorway for targeted drug delivery to brain. For example, high-affinity LATl drug analogs have been developed that showed significantly improved LATl affinity and brain uptake over existing LATl drug substrates (e.g., L-dopa, melphalan, and gabapentin) [40].

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