Leveraging Genetics and Cell Signaling to Decipher Disorders of Excitability
Richard Tsien, Ph.D.
Chair, Department of Neuroscience and Physiology
Director, Neuroscience Institute
Druckenmiller Professor of Neuroscience, Department of Neuroscience and Physiology
Professor, Department of Neurology
NYU Langone Health, Grossman School of Medicine
As a physiologist/neurobiologist, I have long been fascinated by calcium channels. These membrane proteins regulate cellular Ca2+ entry in a voltage-dependent manner and thereby link the realms of electrical signaling and intracellular messengers. A single opening of a Ca2+ channel can allow thousands of calcium ions to enter a cell, thus generating a signal that may control transmitter release, excitability, metabolism, or gene expression. My colleagues and I have been active in discovering and classifying diverse types of Ca2+ channels, including the channels most critical for neurosecretion in the brain. By uncovering N-type Ca2+ channels, we laid the foundation for recent advances in targeting these channels in treatment of certain forms of chronic pain. Our analysis of the biophysical properties of Ca2+ channels led us to propose a mechanism to explain how they manage to be exquisitely selective yet also highly permeant. This mechanism involves high affinity Ca2+ interactions, now worked out at the level of individual amino acid side chains. My colleagues and I have also studied synaptic communication between neurons. Newly developed experimental approaches have allowed us to examine synaptic transmission and plasticity at the level of individual synaptic terminals. We recently found that synaptic activity can cause calmodulin to translocate to the nucleus, thereby activating a transcription factor implicated in long-term memory.
Genetics and Cell Biology/Physiology are both necessary to harvest the insights diseases offer for normal function -- yet their interdisciplinary linkage could be improved. As a cardiac and neuronal functionalist, I have been increasingly motivated by challenges that genetics poses. This holds for genetic studies of families in Sudden Unexpected Death in Childhood, that draw attention to proteins vital to both heart and brain and signaling from the surface membrane to subcellular organelles. Genetics also highlights molecules that control lipid messengers such as lysophosphatidylinositol (LPI), whose receptor GPR55 is a major target of cannabidiol (CBD). I will review how CBD antagonizes LPI, controls excitation-inhibition ratio and curbs seizures. Genetics also teaches us how ion channels and other controllers of cellular function are themselves controlled: by non-coding (largely intronic) regions of genes. I will briefly touch upon new approaches to noncoding variation and their potential application to neuropsychiatric disorders such as schizophrenia.
- To understand how genetic testing illuminates the causes of a devastating disease, Sudden Unexpected Death in Childhood, and identifies dysfunctional calcium signaling as a major cause;
- To chart a course for how genetic analysis of neuropsychiatric disorders such as schizophrenia, Major Depressive Disorder and Bipolar Disorder will spur understanding the impact of non-coding variations in key signaling proteins;
- To appreciate how genetics highlights underappreciated signaling molecules that coordinate excitatory and inhibitory synaptic strength and provide a target for cannabidiol (CBD) action in epilepsy and autism.
This page was last updated on Friday, February 9, 2024