title: Protein kinase CK2 contributes to diminished small conductance Ca2+-activated K+ channel activity of hypothalamic pre-sympathetic neurons in hypertension.
abstract: Small conductance calcium-activated K(+) (SK) channels regulate neuronal excitability. However, little is known about changes in SK channel activity of pre-sympathetic neurons in the hypothalamic paraventricular nucleus (PVN) in essential hypertension. SK channels, calmodulin, and casein kinase II (CK2) form a molecular complex. Because CK2 is up-regulated in the PVN in spontaneously hypertensive rats (SHRs), we hypothesized that CK2 increases calmodulin phosphorylation and contributes to diminished SK channel activity in PVN pre-sympathetic neurons in SHRs. Perforated whole-cell recordings were performed on retrogradely labeled spinally projecting PVN neurons in Wistar-Kyoto (WKY) rats and SHRs. Blocking SK channels with apamin significantly increased the firing rate of PVN neurons in WKY rats but not in SHRs. CK2 inhibition restored the stimulatory effect of apamin on the firing activity of PVN neurons in SHRs. Furthermore, apamin-sensitive SK currents and depolarization-induced medium after-hyperpolarization potentials of PVN neurons were significantly larger in WKY rats than in SHRs. CK2 inhibition significantly increased the SK channel current and medium after-depolarization potential of PVN neurons in SHRs. In addition, CK2-mediated calmodulin phosphorylation level in the PVN was significantly higher in SHRs than in WKY rats. Although SK3 was detected in the PVN, its expression level did not differ significantly between SHRs and WKY rats. Our findings suggest that CK2-mediated calmodulin phosphorylation is increased and contributes to diminished SK channel function of PVN pre-sympathetic neurons in SHRs. This information advances our understanding of the mechanisms underlying hyperactivity of PVN pre-sympathetic neurons and increased sympathetic vasomotor tone in hypertension. Small conductance calcium-activated K(+) (SK) channels, calmodulin, and protein kinase CK2 form a molecular complex and regulate neuronal excitability. Our study suggests that augmented CK2 activity in hypertension can increase calmodulin (CaM) phosphorylation, which leads to diminished SK channel function in pre-sympathetic neurons. Diminished SK channel activity plays a role in hyperactivity of pre-sympathetic neurons in the hypothalamus in hypertension.
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Pachuau
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Li
authors.forename: Shao-Rui
authors.initials: SR
authors.lastname: Chen
authors.forename: Hae-Ahm
authors.initials: HA
authors.lastname: Lee
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Pan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002147:Calmodulin / Q000378:metabolism*; D047390:Casein Kinase II / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013564:Sympathetic Nervous System / Q000502:physiology
chemical_list: D002147:Calmodulin; D024681:Potassium Channels, Calcium-Activated; D047390:Casein Kinase II
keywords: autonomic control; hypertension; hypothalamus; potassium channels; sympathetic nervous system; synaptic plasticity