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KIR4.1: K + Channel Illusion or Reality in the Autoimmune Pathogenesis of Multiple Sclerosis

View Article: PubMed Central - PubMed

ABSTRACT

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Many believe autoimmune pathogenesis plays a key role in MS, but its target(s) remains elusive. A recent study detected autoantibodies against KIR4.1, an ATP-sensitive, inward rectifier potassium channel, in nearly half of the MS patients examined. KIR4.1 channels are expressed in astrocytes. Together with aquaporin 4 (AQP4) water channels, they regulate astrocytic functions vital for myelination. Autoantibodies against AQP4 have been established as a key biomarker for neuromyelitis optica (NMO) and contributed to diagnostic and treatment strategy adjustments. Similarly, identification of KIR4.1 autoantibodies could have high therapeutic values in treating MS. Consistent with its potential role in MS, KIR4.1 dysfunction is implicated in several neurological disorders. However, the enrichment of KIR4.1 autoantibodies in MS patients is questioned by follow-up studies. Further, investigations are needed to clarify this controversy and unravel the underlying mechanisms of MS pathogenesis.

No MeSH data available.


Schematic diagrams of KIR4.1 structure and localization in astrocyte endfeet. (A) Structural diagrams of KIR4.1 (left) and Kv channel (right) subunits. N, the N-terminus; C, the C-terminus; P, the P-loop. The region near the P-loop (residues 83–120) is the putative site recognized by the autoantibodies (Srivastava et al., 2012). 4-Aminopyridine blocks some Kv channels but not KIR channels. (B) Astrocyte endfeet interact with synapses (left), blood vessels (middle) or myelin membranes (right).
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Figure 1: Schematic diagrams of KIR4.1 structure and localization in astrocyte endfeet. (A) Structural diagrams of KIR4.1 (left) and Kv channel (right) subunits. N, the N-terminus; C, the C-terminus; P, the P-loop. The region near the P-loop (residues 83–120) is the putative site recognized by the autoantibodies (Srivastava et al., 2012). 4-Aminopyridine blocks some Kv channels but not KIR channels. (B) Astrocyte endfeet interact with synapses (left), blood vessels (middle) or myelin membranes (right).

Mentions: KIR channels (KIR1 to KIR7) are inwardly rectifying channels, which have a greater tendency to allow K+ ions to flow into, rather than out of, a cell. These KIR channels are not sensitive to dalfampridine [4-aminopyridine (4-AP)], which is currently used for symptomatic treatment of MS, particularly for improving walking in MS patients [see reviews for detailed information (Judge and Bever, 2006; Blight et al., 2014)]. It is believed that the beneficial effect of 4-AP results from restoring axonal conduction by blocking voltage-gated K+ (Kv) channels that are exposed in demyelinated axons. However, 4-AP does not cure MS and blocks many types of Kv channels that are broadly expressed in the nervous system. KIR channels are different from Kv channels in terms of both structure and function. The KIR α-subunit contains two transmembrane domains and one pore-forming loop (Figure 1A). Four KIR α-subunits homo- or hetero-tetramerize to assemble into a functional channel. KIR channels are also insensitive to another Kv channel blocker tetraethylammonium, but can be blocked by Ba2+. Among about 80 genes in the K+ channel superfamily, 15 KIR α-subunits have been identified in humans and rodents with different biophysical and pharmacological properties, and patterns of tissue expression and subcellular localization. KIR4.1 is an intermediate inward rectifier and can bind to adenosine triphosphate (ATP) and PtdIns(4,5)P2 (Hibino et al., 2010).


KIR4.1: K + Channel Illusion or Reality in the Autoimmune Pathogenesis of Multiple Sclerosis
Schematic diagrams of KIR4.1 structure and localization in astrocyte endfeet. (A) Structural diagrams of KIR4.1 (left) and Kv channel (right) subunits. N, the N-terminus; C, the C-terminus; P, the P-loop. The region near the P-loop (residues 83–120) is the putative site recognized by the autoantibodies (Srivastava et al., 2012). 4-Aminopyridine blocks some Kv channels but not KIR channels. (B) Astrocyte endfeet interact with synapses (left), blood vessels (middle) or myelin membranes (right).
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Related In: Results  -  Collection

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Figure 1: Schematic diagrams of KIR4.1 structure and localization in astrocyte endfeet. (A) Structural diagrams of KIR4.1 (left) and Kv channel (right) subunits. N, the N-terminus; C, the C-terminus; P, the P-loop. The region near the P-loop (residues 83–120) is the putative site recognized by the autoantibodies (Srivastava et al., 2012). 4-Aminopyridine blocks some Kv channels but not KIR channels. (B) Astrocyte endfeet interact with synapses (left), blood vessels (middle) or myelin membranes (right).
Mentions: KIR channels (KIR1 to KIR7) are inwardly rectifying channels, which have a greater tendency to allow K+ ions to flow into, rather than out of, a cell. These KIR channels are not sensitive to dalfampridine [4-aminopyridine (4-AP)], which is currently used for symptomatic treatment of MS, particularly for improving walking in MS patients [see reviews for detailed information (Judge and Bever, 2006; Blight et al., 2014)]. It is believed that the beneficial effect of 4-AP results from restoring axonal conduction by blocking voltage-gated K+ (Kv) channels that are exposed in demyelinated axons. However, 4-AP does not cure MS and blocks many types of Kv channels that are broadly expressed in the nervous system. KIR channels are different from Kv channels in terms of both structure and function. The KIR α-subunit contains two transmembrane domains and one pore-forming loop (Figure 1A). Four KIR α-subunits homo- or hetero-tetramerize to assemble into a functional channel. KIR channels are also insensitive to another Kv channel blocker tetraethylammonium, but can be blocked by Ba2+. Among about 80 genes in the K+ channel superfamily, 15 KIR α-subunits have been identified in humans and rodents with different biophysical and pharmacological properties, and patterns of tissue expression and subcellular localization. KIR4.1 is an intermediate inward rectifier and can bind to adenosine triphosphate (ATP) and PtdIns(4,5)P2 (Hibino et al., 2010).

View Article: PubMed Central - PubMed

ABSTRACT

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Many believe autoimmune pathogenesis plays a key role in MS, but its target(s) remains elusive. A recent study detected autoantibodies against KIR4.1, an ATP-sensitive, inward rectifier potassium channel, in nearly half of the MS patients examined. KIR4.1 channels are expressed in astrocytes. Together with aquaporin 4 (AQP4) water channels, they regulate astrocytic functions vital for myelination. Autoantibodies against AQP4 have been established as a key biomarker for neuromyelitis optica (NMO) and contributed to diagnostic and treatment strategy adjustments. Similarly, identification of KIR4.1 autoantibodies could have high therapeutic values in treating MS. Consistent with its potential role in MS, KIR4.1 dysfunction is implicated in several neurological disorders. However, the enrichment of KIR4.1 autoantibodies in MS patients is questioned by follow-up studies. Further, investigations are needed to clarify this controversy and unravel the underlying mechanisms of MS pathogenesis.

No MeSH data available.