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An inside job: how endosomal Na(+)/H(+) exchangers link to autism and neurological disease.

Kondapalli KC, Prasad H, Rao R - Front Cell Neurosci (2014)

Bottom Line: Loss-of-function mutations in eNHE cause hyperacidification of endosomal lumen, as a result of imbalance in pump and leak pathways.Drawing upon insights from model organisms and mammalian cells we show how eNHE affect surface expression and function of membrane receptors and neurotransmitter transporters.These studies lead to cellular models of eNHE activity in pre- and post-synaptic neurons and astrocytes, where they could impact synapse development and plasticity.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, The Johns Hopkins University School of Medicine Baltimore, MD, USA.

ABSTRACT
Autism imposes a major impediment to childhood development and a huge emotional and financial burden on society. In recent years, there has been rapidly accumulating genetic evidence that links the eNHE, a subset of Na(+)/H(+) exchangers that localize to intracellular vesicles, to a variety of neurological conditions including autism, attention deficit hyperactivity disorder (ADHD), intellectual disability, and epilepsy. By providing a leak pathway for protons pumped by the V-ATPase, eNHE determine luminal pH and regulate cation (Na(+), K(+)) content in early and recycling endosomal compartments. Loss-of-function mutations in eNHE cause hyperacidification of endosomal lumen, as a result of imbalance in pump and leak pathways. Two isoforms, NHE6 and NHE9 are highly expressed in brain, including hippocampus and cortex. Here, we summarize evidence for the importance of luminal cation content and pH on processing, delivery and fate of cargo. Drawing upon insights from model organisms and mammalian cells we show how eNHE affect surface expression and function of membrane receptors and neurotransmitter transporters. These studies lead to cellular models of eNHE activity in pre- and post-synaptic neurons and astrocytes, where they could impact synapse development and plasticity. The study of eNHE has provided new insight on the mechanism of autism and other debilitating neurological disorders and opened up new possibilities for therapeutic intervention.

No MeSH data available.


Related in: MedlinePlus

Gene Distribution of patient mutations in NHE6 and NHE9. (A,B) The distribution of NHE6 (A) and NHE9 (B) mutations (missense, non-sense, and in-frame deletions) in N-terminal transmembrane domain and the C-terminal regulatory cytoplasmic domain, listed in Table 1, are displayed. The x-axis indicates amino acid locations of NHE6 and NHE9 proteins, while the y-axis displays the number of published literature reports. All mutations in NHE6 are referred to in relation to longer NHE6.1 isoform (NP_001036002.1).
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Figure 2: Gene Distribution of patient mutations in NHE6 and NHE9. (A,B) The distribution of NHE6 (A) and NHE9 (B) mutations (missense, non-sense, and in-frame deletions) in N-terminal transmembrane domain and the C-terminal regulatory cytoplasmic domain, listed in Table 1, are displayed. The x-axis indicates amino acid locations of NHE6 and NHE9 proteins, while the y-axis displays the number of published literature reports. All mutations in NHE6 are referred to in relation to longer NHE6.1 isoform (NP_001036002.1).

Mentions: The presence of several human disease mutations in the C-terminal tail of eNHE point to an important functional role of this domain (Figure 2; Table 1). For instance, Arg568Gln in the C-terminus of NHE6.1 isoform (Arg536Gln in the shorter NHE6.0 isoform) was identified in three independent reports: two in males with intellectual disability (hemizygous) and one in a female with schizophrenia (heterozygous) (Tarpey et al., 2009; Piton et al., 2011; Santoni et al., 2014). The cytoplasmic C-terminal tail of the NHE lies outside the membrane-embedded transport domain and is not considered essential for ion transport. However, the C-terminal domain may act as a scaffold for binding of multiple proteins that regulate transport kinetics and trafficking. Therefore, the role of interacting proteins at the C-terminus of eNHE is of special interest to understanding the molecular and cellular basis of autism and related neurological disorders.


An inside job: how endosomal Na(+)/H(+) exchangers link to autism and neurological disease.

Kondapalli KC, Prasad H, Rao R - Front Cell Neurosci (2014)

Gene Distribution of patient mutations in NHE6 and NHE9. (A,B) The distribution of NHE6 (A) and NHE9 (B) mutations (missense, non-sense, and in-frame deletions) in N-terminal transmembrane domain and the C-terminal regulatory cytoplasmic domain, listed in Table 1, are displayed. The x-axis indicates amino acid locations of NHE6 and NHE9 proteins, while the y-axis displays the number of published literature reports. All mutations in NHE6 are referred to in relation to longer NHE6.1 isoform (NP_001036002.1).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4066934&req=5

Figure 2: Gene Distribution of patient mutations in NHE6 and NHE9. (A,B) The distribution of NHE6 (A) and NHE9 (B) mutations (missense, non-sense, and in-frame deletions) in N-terminal transmembrane domain and the C-terminal regulatory cytoplasmic domain, listed in Table 1, are displayed. The x-axis indicates amino acid locations of NHE6 and NHE9 proteins, while the y-axis displays the number of published literature reports. All mutations in NHE6 are referred to in relation to longer NHE6.1 isoform (NP_001036002.1).
Mentions: The presence of several human disease mutations in the C-terminal tail of eNHE point to an important functional role of this domain (Figure 2; Table 1). For instance, Arg568Gln in the C-terminus of NHE6.1 isoform (Arg536Gln in the shorter NHE6.0 isoform) was identified in three independent reports: two in males with intellectual disability (hemizygous) and one in a female with schizophrenia (heterozygous) (Tarpey et al., 2009; Piton et al., 2011; Santoni et al., 2014). The cytoplasmic C-terminal tail of the NHE lies outside the membrane-embedded transport domain and is not considered essential for ion transport. However, the C-terminal domain may act as a scaffold for binding of multiple proteins that regulate transport kinetics and trafficking. Therefore, the role of interacting proteins at the C-terminus of eNHE is of special interest to understanding the molecular and cellular basis of autism and related neurological disorders.

Bottom Line: Loss-of-function mutations in eNHE cause hyperacidification of endosomal lumen, as a result of imbalance in pump and leak pathways.Drawing upon insights from model organisms and mammalian cells we show how eNHE affect surface expression and function of membrane receptors and neurotransmitter transporters.These studies lead to cellular models of eNHE activity in pre- and post-synaptic neurons and astrocytes, where they could impact synapse development and plasticity.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, The Johns Hopkins University School of Medicine Baltimore, MD, USA.

ABSTRACT
Autism imposes a major impediment to childhood development and a huge emotional and financial burden on society. In recent years, there has been rapidly accumulating genetic evidence that links the eNHE, a subset of Na(+)/H(+) exchangers that localize to intracellular vesicles, to a variety of neurological conditions including autism, attention deficit hyperactivity disorder (ADHD), intellectual disability, and epilepsy. By providing a leak pathway for protons pumped by the V-ATPase, eNHE determine luminal pH and regulate cation (Na(+), K(+)) content in early and recycling endosomal compartments. Loss-of-function mutations in eNHE cause hyperacidification of endosomal lumen, as a result of imbalance in pump and leak pathways. Two isoforms, NHE6 and NHE9 are highly expressed in brain, including hippocampus and cortex. Here, we summarize evidence for the importance of luminal cation content and pH on processing, delivery and fate of cargo. Drawing upon insights from model organisms and mammalian cells we show how eNHE affect surface expression and function of membrane receptors and neurotransmitter transporters. These studies lead to cellular models of eNHE activity in pre- and post-synaptic neurons and astrocytes, where they could impact synapse development and plasticity. The study of eNHE has provided new insight on the mechanism of autism and other debilitating neurological disorders and opened up new possibilities for therapeutic intervention.

No MeSH data available.


Related in: MedlinePlus