Arthur Karlin

Columbia University


Primary Section: 23, Physiology and Pharmacology
Membership Type: Member (elected 1999)

Biosketch

Arthur Karlin initiated the biochemical characterization of membrane receptors, previously just pharmacological concepts. He showed that the muscle-type nicotinic acetylcholine receptor is a pentamer of four distinct membrane-spanning subunits surrounding a central channel in the specific order αγαδβ. He showed that the α subunits uniquely bear the acetylcholine binding sites and that these include a pair of adjacent cysteinyl residues forming a rare, but conserved vicinal disulfide. To characterize the central cation-conducting channel and its gate, he invented the substituted-cysteine-accessibility method (SCAM), thereafter widely used. He contributed to the eventual determination of the high-resolution structure of this receptor. He also contributed to the determination of the tertiary and quaternary structures of the BK large-conductance potassium channel and of its auxiliary β subunits. He incorporated the BK channel into a mathematical model of the response to pressure and to paracrine and endocrine factors of arterial smooth muscle cells. Born in Philadelphia, Pennsylvania, he received a BA from Swarthmore College in 1957 and a Ph.D. from Rockefeller University in 1962. Since then, he has worked at Columbia University, where he is Higgins Professor of Biochemistry and Molecular Biophysics, Physiology and Cellular Biophysics, and Neurology and Director of the Center for Molecular Recognition.

Research Interests

I am interested in the molecular mechanisms of membrane-protein function. Most of my effort has been on the nicotinic acetylcholine receptors, which were merely pharmacological concepts when I began. My laboratory identified the four different subunits of the muscle-type receptor (2 alpha, 1 beta, 1 gamma, and 1 delta) and showed that they assembled into a pentamer. It also showed that the two acetylcholine binding sites per receptor were associated with the two alpha subunits and later showed that binding-site residues in alpha were close to residues in the gamma and delta subunits, which also contributed to acetylcholine binding. We developed a combined mutational and chemical approach to identify all of the residues that line the ion-conducting channel of the receptor, to detect changes in the structure of the channel as it opened and closed, to map the electrostatic potential profile within the channel, and to locate the channel gate. This approach is being widely applied to other receptors, channels, and transport proteins.

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