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smoking is a thing in the head – nicotine rush too

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When nicotine binds to a neuron, how does the cell know to send the signal that announces a smoker’s high? As with other questions involving good sensations, the answer appears to be sugar.

A University of Southern California study appearing with a commentary in Nature Neuroscience online proposes a role for sugar as the hinge that opens a gate in the cell membrane and brings news of nicotine’s arrival.

Structural biologist Raymond Stevens of The Scripps Research Institute, who was not involved in the study, called it “a landmark accomplishment for the fields of structural biology and neuronal cell signaling.”

Besides substance addiction, Stevens pointed to epilepsy, schizophrenia and depression as targets for improved drugs that could result from the study’s findings.

The study provides the first detailed look at part of the mouse nicotinic acetylcholine receptor (nAChR), one in a large and important group of molecules, known as ion channel proteins, that allow signals to pass between neurons.

The results reveal an important role for the sugar molecules in such proteins.

“Our studies fill a major gap in the field and set a new paradigm,” said Lin Chen, associate professor of molecular and computational biology at USC.

Many existing theories, which do not consider sugar’s role, are probably incomplete, Chen said.

The debate over how signals pass from the outside of a cell to the inside is a long-standing one.

Some researchers had suggested that when a chemical such as nicotine binds to an ion channel protein on the cell surface, the protein starts a “conformational wave” that propagates a signal through the protein body to the cell membrane, Chen said.

But the molecular basis of such a wave in nAChR or any other protein has not been clearly established.

Instead, the Chen group’s study of crystal structure suggested a simple mechanical role for sugar molecules attached to the surface of the receptor.

“They serve as the link between the neurotransmitter binding site and the membrane region where the gate is located,” Chen said.

“The sugar is kind of like a hinge. It’s pulling the door open and closed.”

Cutting the sugar chains stopped the gate’s operation, according to Chen, who said, “The sugar is critical, in my opinion.”

The researchers also found a water molecule deep in the receptor’s core — significant because proteins normally are filled with hydrophobic (water repellent) matter that helps the structure hold its shape, Chen said.

The water molecule may enable the receptor to alter its shape in counterbalance to the bending hinge, said Chen, who explained, “Think of it as a lubricant.”

Previously studied “homologs” of nAChR — proteins that share its structure but not its signaling function — are entirely hydrophobic, Chen said, supporting the theory that the buried water molecule plays a functional role.

Chen called the group’s Nature Neuroscience study “one of the few times that you felt that you connected the dots.”

The study also represents a tour de force of protein crystallography. Homologs of nAChR had been studied at the atomic scale, but not the receptor itself.

Nat Neurosci. 2007 Jul 22; [Epub ahead of print]

Crystal structure of the extracellular domain of nAChR alpha1 bound to alpha-bungarotoxin at 1.94 A resolution.

Dellisanti CD, Yao Y, Stroud JC, Wang ZZ, Chen L.

[1] Molecular and Computation Biology, University of Southern California, 1050 Childs Way, RIH201, Los Angeles, California 90089-2910, USA. [2] Department of Chemistry, University of Southern California, 1050 Childs Way, RIH201, Los Angeles, California 90089-2910, USA. [3] Norris Cancer Center, University of Southern California, 1050 Childs Way, RIH201, Los Angeles, California 90089-2910, USA.

We determined the crystal structure of the extracellular domain of the mouse nicotinic acetylcholine receptor (nAChR) alpha1 subunit bound to alpha-bungarotoxin at 1.94 A resolution. This structure is the first atomic-resolution view of a nAChR subunit extracellular domain, revealing receptor-specific features such as the main immunogenic region (MIR), the signature Cys-loop and the N-linked carbohydrate chain. The toxin binds to the receptor through extensive protein-protein and protein-sugar interactions. To our surprise, the structure showed a well-ordered water molecule and two hydrophilic residues deep in the core of the alpha1 subunit. The two hydrophilic core residues are highly conserved in nAChRs, but correspond to hydrophobic residues in the nonchannel homolog acetylcholine-binding proteins. We carried out site-directed mutagenesis and electrophysiology analyses to assess the functional role of the glycosylation and the hydrophilic core residues. Our structural and functional studies show essential features of the nAChR and provide new insights into the gating mechanism.

PMID: 17643119 [PubMed – as supplied by publisher]

see also:

The Brain And The Nicotine

smoking is a thing in the head…

Written by huehueteotl

July 25, 2007 at 10:29 am

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