title: Cellular mechanisms and behavioral consequences of Kv1.2 regulation in the rat cerebellum.
abstract: The potassium channel Kv1.2 α-subunit is expressed in cerebellar Purkinje cell (PC) dendrites where its pharmacological inhibition increases excitability (Khavandgar et al., 2005). Kv1.2 is also expressed in cerebellar basket cell (BC) axon terminals (Sheng et al., 1994), where its blockade increases BC inhibition of PCs (Southan and Robertson, 1998a). Secretin receptors are also expressed both in PC dendrites and BC axon terminals (for review, see (Yuan et al., 2011). The effect of secretin on PC excitability is not yet known, but, like Kv1.2 inhibitors, secretin potently increases inhibitory input to PCs (Yung et al., 2001). This suggests secretin may act in part by suppressing Kv1.2. Receptor-mediated endocytosis is a mechanism of Kv1.2 suppression (Nesti et al., 2004). This process can be regulated by protein kinase A (PKA) (Connors et al., 2008). Since secretin receptors activate PKA (Wessels-Reiker et al., 1993), we tested the hypothesis that secretin regulates Kv1.2 trafficking in the cerebellum. Using cell-surface protein biotinylation of rat cerebellar slices, we found secretin decreased cell-surface Kv1.2 levels by modulating Kv1.2 endocytic trafficking. This effect was mimicked by activating adenylate cyclase (AC) with forskolin, and was blocked by pharmacological inhibitors of AC or PKA. Imaging studies identified the BC axon terminal and PC dendrites as loci of AC-dependent Kv1.2 trafficking. The physiological significance of secretin-regulated Kv1.2 endocytosis is supported by our finding that infusion into the cerebellar cortex of either the Kv1.2 inhibitor tityustoxin-Kα, or of the Kv1.2 regulator secretin, significantly enhances acquisition of eyeblink conditioning in rats.
authors: Neuroscience Graduate Program, Department of Pharmacology, University of Vermont, Burlington, Vermont 05405, USA.
authors: Michael R
authors: MR
authors: Williams
authors: Jason R
authors: JR
authors: Fuchs
authors: John T
authors: JT
authors: Green
authors: Anthony D
authors: AD
authors: Morielli
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002525:Cerebellar Cortex / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D051663:Kv1.2 Potassium Channel / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology; D009924:Organ Culture Techniques; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012604:Scorpion Venoms / Q000494:pharmacology; D012633:Secretin / Q000502:physiology
chemical_list: C496972:Kcna2 protein, rat; D051663:Kv1.2 Potassium Channel; D009498:Neurotoxins; D012604:Scorpion Venoms; D012633:Secretin; C003609:tityustoxin