SUMMARY
Research by Steven M. Sine, Ph.D., in his Receptor Biology Laboratory, investigates the function of neurotransmitter receptors — a class of signaling proteins that mediate moment-to-moment communication between cells in the central and peripheral nervous systems. Neurotransmitter receptors are crucial for a wide range of physiological processes and are targets for diseases and therapeutic drugs. Despite the profound physiological significance of neurotransmitter receptors, mechanisms by which they function at the molecular level and how they interact with drugs and physiological modulators remain largely unknown.
The overarching goal of Dr. Sine's laboratory is to understand biophysical and molecular mechanisms by which rapidly acting neurotransmitter receptors function in normal and disease conditions and in the presence of therapeutic drugs.
To address gaps in the understanding of neurotransmitter receptor physiology, pathology and modulation, the laboratory employs state-of-the-art biophysical methods to monitor single receptor molecules functioning in real time, and alters their structures with molecular precision to decipher the physical mechanisms underlying function and identify pivotal molecular structures that underpin function.
Focus areas
- Superfamily of rapidly acting neurotransmitter receptors. The Sine laboratory focuses on nicotinic acetylcholine receptors, which are members of a large superfamily of neurotransmitter receptors responsible for rapid signaling throughout the body. Each member of the superfamily is composed of five protein subunits, which arise from either a single gene or multiple related genes, and each acts as a chemically activated electrical switch by virtue of a neurotransmitter binding site situated on the outside of the cell and an ion channel embedded in the cell membrane. Binding of the neurotransmitter opens the ion channel, which lets ions flow in or out of the cell, conferring electrical excitability. Mechanistic principles delineated for nicotinic receptors will contribute to understanding the physiology of each member of the receptor superfamily.
- Nicotinic acetylcholine receptors from skeletal muscle. Muscle nicotinic receptors mediate all voluntary motor movement, and are altered in muscle weakness disorders such as congenital and autoimmune myasthenia. They are also targets for a host of paralytic toxins found in nature, as well as drugs used to prevent muscle contraction during surgical procedures. Current research aims to quantitatively describe the biophysical mechanism by which the neurotransmitter acetylcholine (ACh) activates the muscle receptor. This mechanism will form the basis for diagnosis and treatment of patients with congenital myasthenic syndromes.
- Alpha7 nicotinic acetylcholine receptors. Alpha7 receptors are abundant in neuronal and non-neuronal cells, and mediate both synaptic and nonsynaptic cell-cell signaling. Signaling via alpha7 contributes to cognition, sensory processing, memory and reward, and the alpha7 receptor is implicated in neurodegenerative and psychiatric diseases and inflammation. Current research aims to determine how the interplay among the five subunits of alpha7 transduces binding of ACh into opening of the ion channel, and mechanisms by which physiological modulators and drugs amplify alpha7's response to ACh. The findings will delineate mechanisms by which alpha7 mediates synaptic and nonsynaptic transmission. These mechanisms will ultimately contribute to diagnosis and treatment of neurodegenerative, psychiatric and inflammatory disorders.
- Alpha-4-beta-2 nicotinic receptors from neurons. Alpha-4-beta-2 receptors are the most abundant nicotinic receptors in the brain and are the initial target of the addictive drug nicotine. Current research aims to understand how the number of alpha-4 and beta-2 subunits in an individual receptor determine the receptor's response to ACh and nicotine and how the number of each subunit and its position relative to the other subunits confer specificity for modulating drugs. The findings will contribute to understanding mechanisms of nicotine addiction and form bases to develop drugs to treat smoking cessation.
Significance to patient care
Diseases of the nervous system impact an estimated 50 million Americans each year and levy enormous personal and economic burdens. They comprise common disorders such as stroke, epilepsy, Parkinson's and Alzheimer's diseases, schizophrenia, depression, and drug addiction, as well as many rare, predominantly familial disorders. Common to virtually all of these disorders is impaired cell-to-cell signaling. By delineating mechanisms by which neurotransmitter receptors signal, studies in the Sine lab contribute to understanding function of the nervous system and to diagnosis and treatment of neurological diseases.
Professional highlights
- Member, National Institutes of Health (NIH) study sections, 2003-2007
- Recipient, Jacob Javits merit award, NIH, 2001-2008