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Olfactory System:

olfactoryA major focus of our laboratory is olfactory signaling and the molecular mechanism that regulate our sense of smell. In the nose, neurons involved in smell have many cilia, hair-like projections into the nasal cavity, which contain all of the proteins responsible for detecting odors. The goal of our laboratory is to understand how olfactory proteins get to the cilia and why genetic mutations in proteins of these cilia result in the loss of smell.   Specifically we hope to elucidate the mechanisms underlying the transport of odorant signaling proteins into mammalian olfactory cilia and their alterations in cilia-related disorders. Olfactory dysfunction in the general population is frequent, affecting at least 2.5 million people in the U.S. alone. In at least 20% of the cases the etiology of the chemosensory disturbance cannot be identified. Recently, we have demonstrated olfactory dysfunction as a clinical manifestation of an emerging class of human genetic disorders, termed ciliopathies, which involve defects in ciliary assembly and/or protein transport. Given the plasticity of the olfactory system and its regenerative properties, olfactory sensory neurons (OSNs) undergo a continual process of ciliogenesis and protein transport which is critical for olfactory function. Intrinsic mechanisms are present in OSNs that direct cell surface localization and selective ciliary compartmentalization of olfactory transduction proteins where the enrichment of signaling proteins in the cilia of olfactory sensory neurons (OSNs) is essential for odor detection. Remarkably, the mechanisms and molecular machinery necessary for ciliary transport in OSNs are virtually unexplored. Currently a major focus in the laboratory is understanding the mechanisms of protein trafficking and localization in olfactory sensory neurons. In particular we are interested in the mechanisms by which transmembrane signaling proteins, such as CNG channels and odorant receptors, localize to the cilia of olfactory sensory neurons.

 

 

Cardiovascular System:
Projects in our laboratory are focused on the identification of novel targets for the treatment of cardiac arrhythmias. In particular, we are interested in therapies for atrial fibrillation, which is the most common cardiac arrhythmia affecting more than 2 million Americans. This electrical instability in the human heart can occur through a primary genetic defect in ion channel function or an acquired disorder attributable to ion channel dysregulation. We are interested in the regulation of voltage-gated potassium  (Kv) channels that are vital for atrial repolarization in the human heart. Work in our laboratory is devoted to understanding the details of Kv channel regulation, trafficking, and pharmacological modulation and how this is all integrated into the broader context of normal cardiomyocyte signaling and the pathogenesis of disease. 

 


Ion Channel Trafficking: trafficking
Our goal is to elucidate the precise mechanisms regulating cell-surface level, localization and targeting of cardiovascular ion channels. Kv1.5 is a prominent cardiovascular K+ channel that is vital for atrial repolarization in the human heart and the regulation of vascular tone in multiple peripheral vascular beds. Therefore, there is significant interest in Kv1.5 as a potential pharmacological target for diseases such as chronic atrial fibrillation and chronic hypoxic pulmonary arterial hypertension (PAH). Recently, mutations in Kv1.5 have been shown to cause human atrial fibrillation, while alterations in its cell surface expression contribute to the pathophysiology of paroxysmal and persistent atrial fibrillation as well as PAH.  Remarkably, despite the clear links between changes in Kv1.5 surface expression and cardiovascular disease, relatively little is known regarding the mechanisms controlling its plasma membrane targeting or localization.  Recently, we have discovered an unexpected dynamic trafficking of Kv1.5 at the myocyte plasma membrane and demonstrated a role for internalization and recycling in the maintenance of steady-state ion channel surface levels. Ongoing projects in the laboratory focus on identifying the molecular machinery and the regulatory mechanisms controlling Kv1.5 surface levels in atrial myocytes and therapeutic strategies designed to manipulate specific ion channel trafficking pathways.

 

 

Post-Translational Modifications of Ion Channels:sumo
Our goal is to understand the basic mechanisms that regulate the biogenesis and function of ion channels through post-translational modifications and their dysregulation in disease.  A wide array of cellular responses are dependent on appropriately regulated Kv channel function at the plasma membrane. Post-translational modifications provide a likely mechanism for precise spatial and temporal regulation of Kv channel activity in response to diverse physiological and pathophysiological stimuli.  Despite our growing knowledge of the structure and function of Kv channels, the nature and significance of post-translational mechanisms acting on them remain poorly understood yet represent potential therapeutic intervention points.  Recent work in our laboratory has identified several novel post-translational modifications to Kv1.5 that include thioacylation and Sumoylation. Current projects in the laboratory focus on the physiological relevance of these modifications and their in vivo regulation.

 

 

Protein-lipid interactions in ion channel targeting and function:
We are particularity interested in the factors that influence K+ channel localization. Ion channel regulation within neuronal and muscle membranes is an important determinant of electrical excitability.   Voltage-gated K+ channels (Kv) play an important role in setting the resting membrane potential and determining repolarization in the nervous system and therefore represent significant therapeutic targets in the treatment of a growing list of diseases. Importantly, the subcellular localization of K+ channels is necessary for proper electrical signaling.  Within the brain, Kv channels often show not only polarized distribution to either axons or dendrites, but also isoform specific localization within dendrites alone. Thus there exist specific sorting mechanisms for restricting lateral distribution within the plasma membrane. While progress has been made in identifying elements involved in channel targeting, clustering and anchoring, it is not yet clear how the number and location of channel complexes within the plane of the membrane are determined and how this compartmentalization affects channel function.   Recently, we were the first to show that Kv channels differentially target to specialized microdomains, termed lipid rafts, within the plane of the plasma membrane. These domains are enriched in cholesterol and sphingolipids and concentrate a number of signal transduction enzymes. The differential targeting of Kv channels to lipid rafts represents a novel mechanism both for the subcellular sorting of K+ channels to regions of the membrane rich in signaling complexes and for modulating channel properties via lipid based signaling mechanisms. Several ongoing projects in our lab combine techniques in molecular biology, protein chemistry, and electrophysiology to examine the mechanisms and functional significance of channel targeting to plasma membrane microdomains.

rafts


  © 2009 Jeffrey R. Martens