Long Polyamines Act as Cofactors in PIP2 Activation of Inward Rectifier Potassium (Kir2.1) Channels. Export

@article{citeulike:436364, abstract = {Phosphatidylinosital-4,5-bisphosphate (PIP(2)) acts as an essential factor regulating the activity of all Kir channels. In most Kir members, the dependence on PIP(2) is modulated by other factors, such as protein kinases (in Kir1), G(betagamma) (in Kir3), and the sulfonylurea receptor (in Kir6). So far, however, no regulator has been identified in Kir2 channels. Here we show that polyamines, which cause inward rectification by selectively blocking outward current, also regulate the interaction of PIP(2) with Kir2.1 channels to maintain channel availability. Using spermine and diamines as polyamine analogs, we demonstrate that both spontaneous and PIP(2) antibody-induced rundown of Kir2.1 channels in excised inside-out patches was markedly slowed by long polyamines; in contrast, polyamines with shorter chain length were ineffective. In K188Q mutant channels, which have a low PIP(2) affinity, application PIP(2) (10 muM) was unable to activate channel activity in the absence of polyamines, but markedly activated channels in the presence of long diamines. Using neomycin as a measure of PIP(2) affinity, we found that long polyamines were capable of strengthening either the wild type or K188Q channels' interaction with PIP(2). The negatively charged D172 residue inside the transmembrane pore region was critical for the shift of channel-PIP(2) binding affinity by long polyamines. Sustained pore block by polyamines was neither sufficient nor necessary for this effect. We conclude that long polyamines serve a dual role as both blockers and coactivators (with PIP(2)) of Kir2.1 channels.}, address = {Correspondence to James N. Weiss: jweiss@mednet.ucla.edu.}, author = {Xie, L. H. and John, S. A. and Ribalet, B. and Weiss, J. N.}, citeulike-article-id = {436364}, citeulike-linkout-0 = {http://dx.doi.org/10.1085/jgp.200509380}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/16316973}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=16316973}, doi = {10.1085/jgp.200509380}, issn = {0022-1295}, journal = {J Gen Physiol}, keywords = {1-12-dodecanediamine, 110-decanediamine, da10, da12, phosphatidylinositol, pip2, polyamines}, month = {December}, number = {6}, pages = {541--549}, posted-at = {2005-12-12 21:27:54}, priority = {2}, title = {Long Polyamines Act as Cofactors in PIP2 Activation of Inward Rectifier Potassium (Kir2.1) Channels.}, url = {http://dx.doi.org/10.1085/jgp.200509380}, volume = {126}, year = {2005} }

TY - JOUR ID - citeulike:436364 L3 - citeulike-article-id:436364 N2 - Phosphatidylinosital-4,5-bisphosphate (PIP(2)) acts as an essential factor regulating the activity of all Kir channels. In most Kir members, the dependence on PIP(2) is modulated by other factors, such as protein kinases (in Kir1), G(betagamma) (in Kir3), and the sulfonylurea receptor (in Kir6). So far, however, no regulator has been identified in Kir2 channels. Here we show that polyamines, which cause inward rectification by selectively blocking outward current, also regulate the interaction of PIP(2) with Kir2.1 channels to maintain channel availability. Using spermine and diamines as polyamine analogs, we demonstrate that both spontaneous and PIP(2) antibody-induced rundown of Kir2.1 channels in excised inside-out patches was markedly slowed by long polyamines; in contrast, polyamines with shorter chain length were ineffective. In K188Q mutant channels, which have a low PIP(2) affinity, application PIP(2) (10 muM) was unable to activate channel activity in the absence of polyamines, but markedly activated channels in the presence of long diamines. Using neomycin as a measure of PIP(2) affinity, we found that long polyamines were capable of strengthening either the wild type or K188Q channels' interaction with PIP(2). The negatively charged D172 residue inside the transmembrane pore region was critical for the shift of channel-PIP(2) binding affinity by long polyamines. Sustained pore block by polyamines was neither sufficient nor necessary for this effect. We conclude that long polyamines serve a dual role as both blockers and coactivators (with PIP(2)) of Kir2.1 channels. IS - 6 JF - J Gen Physiol SN - 0022-1295 AD - Correspondence to James N. Weiss: jweiss@mednet.ucla.edu. EP - 549 TI - Long Polyamines Act as Cofactors in PIP2 Activation of Inward Rectifier Potassium (Kir2.1) Channels. VL - 126 SP - 541 KW - 1-12-dodecanediamine KW - 110-decanediamine KW - da10 KW - da12 KW - phosphatidylinositol KW - pip2 KW - polyamines AU - Xie, LH AU - John, SA AU - Ribalet, B AU - Weiss, JN PY - 2005/12// UR - http://dx.doi.org/10.1085/jgp.200509380 ER -