Anthony D. Morielli, Ph.D.

Research interests:

     Potassium channel regulation by G protein-coupled receptors (GPCRs) plays a central role in the physiology of excitable cells.  In the nervous system, GPCR-regulated potassium currents influence the strength of synaptic connections and the integration of synaptic input.  To investigate the molecular mechanisms by which GPCRs modulate the activiteis of defined potassium channels, I have utilized two in vitro exression systems, Xenopus oocytes and human embryonic kidney 293 cells, in which a single type of potassium channel can be studied.  I have focused on the GPCR-mediated regulation of the shaker family potassium channel, Kv1.2, a delayed rectifier potassium channel found in cardiac atrial muscle and throughout the central nervous system.  We have found that Kv1.2 is under positive regulation via GPCR-activated PKA and negative regulation through a relatively unexplored GPCR pathway involving the activation of nonreceptor tyrosine kinases.   My research has focused on understanding the physiological and molecular mechanisms by which these processes occur.

     In addition to tyrosine kinases, I have found that tyrosine phosphatase activity also plays a central role in GPCR mediated suppression of Kv1.2.  The tyrosine kinase inhibitors pervanadate or orthovanadate strongly potentiate GPCR mediates suppression of Kv1.2.   Further, in some cases, GPCR activation can cause a PKA independent increase in Kv1.2 activity.  In collaboration with Bill Tsai, I have found that this increase appears to result from the activation of a receptor tyrosine kinase by a GPCR.  This research indicates that GPCR activation results an increase in both tyrosine kinase and tyrosine phosphatase activity.  The ultimate effect of GPCR activation on Kv1.2 current may thererfore depend on a dynamic balance between these two opposing signals.

     In collaboration with Teresa Cachero, I have found that tyrosine kinase dependent suppression of Kv1.2 involves the association of the small guanine nucleotide binding protein, RhoA with the channel protein's amino terminus.  RhoA may act to suppress Kv1.2 channel activity by virtue of its direct physical association, by recruiting RhoA activated kinases to the channel, by re-organizing the actin cytoskeleton in the vicinity of the channel, or by any combination of these.  I am especially interested in the role of the actin cytoskeleton in Kv1.2 channel activity and suppression since disruption of the actin cytoskeleton also disrupts both normal channel activity as well as GPCR-mediated channel suppression.  Exploring the role of the cytoskeleton in Kv1.2 channel activity is the focus of my current research efforts.