Research Interests

Structure-Function relationship of Transient Receptor Potential (TRP) ion channels in molecular complexes with homo-polymers

TRP channels play important roles in the perception of the environment. They respond to a number of physical and chemical stimuli and demonstrate an unusual complexity of regulatory modes.

The TRP family proteins are calcium-permeable channels and participate in a great variety of physiological and pathological processes. Physiological processes with involvement of TRP channels include thermosensation, nociception, mechanosensation, taste, vision, fertilization, intra- and extracellular Ca2+ and Mg2+ homeostasis.

Accumulated evidence also indicates involvement of TRP channels in pathophysiology and development of various diseases due to the multifunctional cellular responses carried by these proteins. Currently, we are interested in understanding the role of TRP channel in cancel cells. Expression of various TRP channels in different carcinogenic tissues has continually been reported, moreover some of the TRPs have originally been cloned from cancer cells. However, no clear mechanism of function of TRP channels and their roles in tumor-related regulations have immerged thus far. The role of TRP channels in processes like cell proliferation, differentiation, apoptosis, migration, and invasion upon cancer progression has yet to be understood.

Understanding the interplay of TRP channels and cancer cells is also critical at the level of molecular organization of these channels. It has become evident now that TRP channels are engaged in the molecular complexes, where their function can significantly be altered by the homo-polymers, like inorganic polyphosphate (polyP) and polyhydroxybutyrate (PHB).

Zakharian graphicPosttranslational modification of the TRPM8 protein with polyhydroxybutyrate (PHB) is required for the channel function.

The cold and menthol receptor, TRPM8, is a representative member of this channel family, and exhibits a broad variety of functional modes with a number of allosteric regulators. The versatility of TRPM8 is also apparent at the level of molecular organization. Previously, we demonstrated that the functional TRPM8 channel exists as a complex with polyP, where the polymer is associated with the TRPM8 protein via ionic interactions and it plays a role in the gating of the channel. In our recent studies we also aimed to identify.

PHB-modification sites on the TRPM8 protein and determine the role of PHB in TRPM8 channel function. The polyester PHB forms a structural/functional complex with TRPM8 and is involved in temperature-induced conformational changes of the protein.

TRPM8 channels expressed in sensory neurons are responsible for perception of cold temperatures. However, originally the TRPM8 protein has been detected in human prostate and its gene is considered as a prostate-specific gene. The role of TRPM8 in prostate cancer is poorly understood. The channel could be involved in calcium signaling regulation, and the balance of the TRPM8 channel expression and localization in plasma membrane and endoplasmic reticulum membrane could play important role in intracellular calcium concentrations and subsequent induction of apoptosis. These studies might help in shedding light on the role of TRP channels in cancer and further imply this information in therapeutics or drug-target interventions.