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CHRFAM7A, a human-specific and partially duplicated ?7-nicotinic acetylcholine receptor gene with the potential to specify a human-specific inflammatory response to injury.

ABSTRACT: Conventional wisdom presumes that the ?7nAChR product of CHRNA7 expression mediates the ability of the vagus nerve to regulate the inflammatory response to injury and infection. Yet, 15 years ago, a 2nd structurally distinct and human-specific ?7nAChR gene was discovered that has largely escaped attention of the inflammation research community. The gene, originally called dup?7nAChR but now known as CHRFAM7A, has been studied exhaustively in psychiatric research because of its association with mental illness. However, dup?7nAChR/CHRFAM7A expression is relatively low in human brain but elevated in human leukocytes. Furthermore, ?7nAChR research in human tissues has been confounded by cross-reacting antibodies and nonspecific oligonucleotide primers that crossreact in immunoblotting, immunohistochemistry, and RT-PCR. Yet, 3 independent reports show the human-specific CHRFAM7A changes cell responsiveness to the canonical ?7nAChR/CHRNA7 ion-gated channel. Because of its potential for the injury research community, its possible significance to human leukocyte biology, and its relevance to human inflammation, we review the discovery and structure of the dup?7nAChR/CHRFAM7A gene, the distribution of its mRNA, and its biologic activities and then discuss its possible role(s) in specifying human inflammation and injury. In light of emerging concepts that point to a role for human-specific genes in complex human disease, the existence of a human-specific ?7nAChR regulating inflammatory responses in injury underscores the need for caution in extrapolating findings in the ?7nAChR literature to man. To this end, we discuss the translational implications of a uniquely human ?7nAChR-like gene on new drug target discovery and therapeutics development for injury, infection, and inflammation.

SUBMITTER: Costantini TW

PROVIDER: S-EPMC4304420 | biostudies-other | 2015 Feb

REPOSITORIES: biostudies-other

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CHRFAM7A, a human-specific and partially duplicated α7-nicotinic acetylcholine receptor gene with the potential to specify a human-specific inflammatory response to injury.

Costantini Todd W TW Dang Xitong X Coimbra Raul R Eliceiri Brian P BP Baird Andrew A

Journal of leukocyte biology 20141203 2

Conventional wisdom presumes that the α7nAChR product of CHRNA7 expression mediates the ability of the vagus nerve to regulate the inflammatory response to injury and infection. Yet, 15 years ago, a 2nd structurally distinct and human-specific α7nAChR gene was discovered that has largely escaped attention of the inflammation research community. The gene, originally called dupα7nAChR but now known as CHRFAM7A, has been studied exhaustively in psychiatric research because of its association with m ...[more]

PMID: 25473097

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Project description:The neuronal alpha4beta2 nicotinic acetylcholine receptor (nAChR) is one of the most widely expressed nAChR subtypes in the brain. Its subunits have high sequence identity (54 and 46% for alpha4 and beta2, respectively) with alpha and beta subunits in Torpedo nAChR. Using the known structure of the Torpedo nAChR as a template, the closed-channel structure of the alpha4beta2 nAChR was constructed through homology modeling. Normal-mode analysis was performed on this closed structure and the resulting lowest frequency mode was applied to it for a "twist-to-open" motion, which increased the minimum pore radius from 2.7 to 3.4 A and generated an open-channel model. Nicotine could bind to the predicted agonist binding sites in the open-channel model but not in the closed one. Both models were subsequently equilibrated in a ternary lipid mixture via extensive molecular dynamics (MD) simulations. Over the course of 11 ns MD simulations, the open channel remained open with filled water, but the closed channel showed a much lower water density at its hydrophobic gate comprised of residues alpha4-V259 and alpha4-L263 and their homologous residues in the beta2 subunits. Brownian dynamics simulations of Na+ permeation through the open channel demonstrated a current-voltage relationship that was consistent with experimental data on the conducting state of alpha4beta2 nAChR. Besides establishment of the well-equilibrated closed- and open-channel alpha4beta2 structural models, the MD simulations on these models provided valuable insights into critical factors that potentially modulate channel gating. Rotation and tilting of TM2 helices led to changes in orientations of pore-lining residue side chains. Without concerted movement, the reorientation of one or two hydrophobic side chains could be enough for channel opening. The closed- and open-channel structures exhibited distinct patterns of electrostatic interactions at the interface of extracellular and transmembrane domains that might regulate the signal propagation of agonist binding to channel opening. A potential prominent role of the beta2 subunit in channel gating was also elucidated in the study.

Dataset Information

CHRFAM7A, a human-specific and partially duplicated ?7-nicotinic acetylcholine receptor gene with the potential to specify a human-specific inflammatory response to injury.

Publications

CHRFAM7A, a human-specific and partially duplicated α7-nicotinic acetylcholine receptor gene with the potential to specify a human-specific inflammatory response to injury.

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