A Current Regulation by Dipeptidyl Peptidase-Like Proteins Dipeptidyl peptidase like (DPL) proteins, DPP6 and DPP10, regulate Kv4 channel expression and functional properties and are essential components of the native neuronal ISA, somatodendritic A current along with Kv4 alpha subunits and KChIP auxiliary subunits. Without DPL expression, ISA is severely disrupted with reduced current expression and abnormal activation and inactivation properties. In this project we will test the hypothesis that specific conserved functional domains in the first two exons of DPL genes regulate the interaction of DPL proteins with Kv4 channels proteins and determine the functional properties of the channel complex. These studies will provide important new information about the molecular mechanisms that regulate the functional properties of neurons and likely will be important for our understanding of the molecular mechanisms underlying disease processes such as ALS, autism spectrum disorder, asthma, and other regulatory pathways that DPL proteins have been implicated in. In this project we will address the following aims to better understand the molecular mechanisms involved in the regulation of A currents by DPL proteins.
Aim 1 : Test the hypothesis that DPP6a and DPP10a accelerate inactivation using a novel N-terminal motif that shares a common underlying molecular mechanism with other N-type inactivation domains.
Aim 2 : Test the Hypothesis that multiple intermediate states are experienced during N-type inactivation by DPP6a and DPP10a.
Aim 3 : Test the hypothesis that specific DPL residues in transmembrane and peri-transmembrane region modulate Kv4 channel activation gating.
Dipeptidyl peptidase-like (DPL) proteins are expressed at high levels in the brain and human genetic linkage studies have linked DPL genetic variations to asthma, amyotropic lateral sclerosis, and autism spectrum disorders. A known function of DPL proteins is to bind and regulate potassium channels. In this project we will characterize the molecular mechanisms that underlie the regulation of potassium channels by DPL proteins.
|Jerng, Henry H; Pfaffinger, Paul J (2014) S-glutathionylation of an auxiliary subunit confers redox sensitivity to Kv4 channel inactivation. PLoS One 9:e93315|
|Prince, Alison; Pfaffinger, Paul J (2013) Conserved N-terminal negative charges support optimally efficient N-type inactivation of Kv1 channels. PLoS One 8:e62695|
|Pfaffinger, Paul J (2013) A conserved pre-block interaction motif regulates potassium channel activation and N-type inactivation. PLoS One 8:e79891|
|Kunjilwar, Kumud; Qian, Yan; Pfaffinger, Paul J (2013) Functional stoichiometry underlying KChIP regulation of Kv4.2 functional expression. J Neurochem 126:462-72|
|Nadin, Brian M; Pfaffinger, Paul J (2013) A new TASK for Dipeptidyl Peptidase-like Protein 6. PLoS One 8:e60831|
|Jerng, Henry H; Pfaffinger, Paul J (2012) Incorporation of DPP6a and DPP6K variants in ternary Kv4 channel complex reconstitutes properties of A-type K current in rat cerebellar granule cells. PLoS One 7:e38205|
|Nadin, Brian M; Pfaffinger, Paul J (2010) Dipeptidyl peptidase-like protein 6 is required for normal electrophysiological properties of cerebellar granule cells. J Neurosci 30:8551-65|
|Prince-Carter, Alison; Pfaffinger, Paul J (2009) Multiple intermediate states precede pore block during N-type inactivation of a voltage-gated potassium channel. J Gen Physiol 134:15-34|
|Jerng, Henry H; Dougherty, Kevin; Covarrubias, Manuel et al. (2009) A novel N-terminal motif of dipeptidyl peptidase-like proteins produces rapid inactivation of KV4.2 channels by a pore-blocking mechanism. Channels (Austin) 3:448-61|