東華大學圖書館 |

語系: 繁體中文

說明(常見問題)

回圖書館首頁

手機版館藏查詢

登入

回首頁

切換: 標籤 | MARC模式 | ISBD

Dynamic Control of the Cardiac Calci...

Cleary, Sean R.

FindBook

Google Book

Amazon

博客來

Dynamic Control of the Cardiac Calcium Pump.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Dynamic Control of the Cardiac Calcium Pump./
作者:	Cleary, Sean R.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2023,
面頁冊數:	174 p.
附註:	Source: Dissertations Abstracts International, Volume: 85-01, Section: B.
Contained By:	Dissertations Abstracts International85-01B.
標題:	Molecular biology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30567382
ISBN:	9798379943783

Dynamic Control of the Cardiac Calcium Pump.
Cleary, Sean R.

Dynamic Control of the Cardiac Calcium Pump. - Ann Arbor : ProQuest Dissertations & Theses, 2023 - 174 p.

Source: Dissertations Abstracts International, Volume: 85-01, Section: B.

Thesis (Ph.D.)--Loyola University Chicago, 2023.

The sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) sequesters Ca2+ into the endoplasmic reticulum of cells to establish a reservoir for Ca2+ signaling. In the heart, the activity of this transporter is tightly controlled via direct interactions with two competing regulatory micropeptides: phospholamban (PLB) and dwarf open reading frame (DWORF). PLB inhibits SERCA, while DWORF activates SERCA. These competing interactions determine cardiac performance by modulating the Ca2+ signals that drive the contraction/relaxation cycle. Previous studies indicated these SERCA-micropeptide interactions are Ca2+-sensitive; SERCA binds PLB more avidly at low cytoplasmic [Ca2+] but binds DWORF better when [Ca2+] is high. Here, FRET-microscopy demonstrated that this opposing Ca2+-sensitivity drives dynamic shifts in SERCA-micropeptide binding during cellular Ca2+ elevations. Evaluating the rates of these equilibrium shifts revealed that PLB monomers freed from SERCA during Ca2+ elevations rapidly oligomerize into PLB pentamers. These stable oligomers unbind slowly, delaying the rebinding of inhibitory PLB monomers to SERCA after Ca2+ elevations. In contrast, DWORF is exchanged rapidly on and off SERCA with respect to the rise and fall of transient Ca2+ signals. Computational modeling revealed that the slow unbinding of PLB pentamers causes PLB monomers to accumulate in these complexes during accelerated cardiac pacing. We propose that this accumulation of PLB pentamers decreases availability of inhibitory PLB monomers to bind SERCA and contributes to an increase in the contractile force of cardiac muscle at faster heart rates. Moreover, we demonstrated that a mutation of PLB, Arginine 14 deletion, which is associated with lethal dilated cardiomyopathy, further stabilizes PLB pentamers and blunts these dynamics adjustments to Ca2+ handling. It was also determined that the reciprocal Ca2+ sensitivity of PLB and DWORF results from their preference for binding different intermediate conformations that SERCA samples during Ca2+ transport. Specifically, PLB had the highest affinity for the ATP-bound state of SERCA, which prevails at low [Ca2+]. This result led us to hypothesize that tight binding of PLB to the ATP-bound state of SERCA may relate to its inhibitory effect on SERCA, decreasing the pump's apparent Ca2+ affinity. Using a 2-color SERCA biosensor to report changes in SERCA conformation during Ca2+ binding by changes in intramolecular FRET, we tested whether PLB reduces SERCA Ca2+ affinity in the presence and absence of nucleotide. The results suggest that PLB inhibits SERCA through reversing an allosteric activation of the pump by ATP.

ISBN: 9798379943783Subjects--Topical Terms:

517296
Molecular biology.
Subjects--Index Terms:

Endoplasmic reticulum

Dynamic Control of the Cardiac Calcium Pump.
LDR:03789nmm a2200385 4500 001 2401090
005 20241015112521.5
006 m o d
007 cr#unu||||||||
008 251215s2023 ||||||||||||||||| ||eng d
020 $a 9798379943783
035 $a (MiAaPQ)AAI30567382
035 $a AAI30567382
035 $a 2401090
040 $a MiAaPQ $c MiAaPQ
100 1 $a Cleary, Sean R. $3 3771151
245 1 0 $a Dynamic Control of the Cardiac Calcium Pump.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2023
300 $a 174 p.
500 $a Source: Dissertations Abstracts International, Volume: 85-01, Section: B.
500 $a Advisor: Robia, Seth.
502 $a Thesis (Ph.D.)--Loyola University Chicago, 2023.
520 $a The sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) sequesters Ca2+ into the endoplasmic reticulum of cells to establish a reservoir for Ca2+ signaling. In the heart, the activity of this transporter is tightly controlled via direct interactions with two competing regulatory micropeptides: phospholamban (PLB) and dwarf open reading frame (DWORF). PLB inhibits SERCA, while DWORF activates SERCA. These competing interactions determine cardiac performance by modulating the Ca2+ signals that drive the contraction/relaxation cycle. Previous studies indicated these SERCA-micropeptide interactions are Ca2+-sensitive; SERCA binds PLB more avidly at low cytoplasmic [Ca2+] but binds DWORF better when [Ca2+] is high. Here, FRET-microscopy demonstrated that this opposing Ca2+-sensitivity drives dynamic shifts in SERCA-micropeptide binding during cellular Ca2+ elevations. Evaluating the rates of these equilibrium shifts revealed that PLB monomers freed from SERCA during Ca2+ elevations rapidly oligomerize into PLB pentamers. These stable oligomers unbind slowly, delaying the rebinding of inhibitory PLB monomers to SERCA after Ca2+ elevations. In contrast, DWORF is exchanged rapidly on and off SERCA with respect to the rise and fall of transient Ca2+ signals. Computational modeling revealed that the slow unbinding of PLB pentamers causes PLB monomers to accumulate in these complexes during accelerated cardiac pacing. We propose that this accumulation of PLB pentamers decreases availability of inhibitory PLB monomers to bind SERCA and contributes to an increase in the contractile force of cardiac muscle at faster heart rates. Moreover, we demonstrated that a mutation of PLB, Arginine 14 deletion, which is associated with lethal dilated cardiomyopathy, further stabilizes PLB pentamers and blunts these dynamics adjustments to Ca2+ handling. It was also determined that the reciprocal Ca2+ sensitivity of PLB and DWORF results from their preference for binding different intermediate conformations that SERCA samples during Ca2+ transport. Specifically, PLB had the highest affinity for the ATP-bound state of SERCA, which prevails at low [Ca2+]. This result led us to hypothesize that tight binding of PLB to the ATP-bound state of SERCA may relate to its inhibitory effect on SERCA, decreasing the pump's apparent Ca2+ affinity. Using a 2-color SERCA biosensor to report changes in SERCA conformation during Ca2+ binding by changes in intramolecular FRET, we tested whether PLB reduces SERCA Ca2+ affinity in the presence and absence of nucleotide. The results suggest that PLB inhibits SERCA through reversing an allosteric activation of the pump by ATP.
590 $a School code: 0112.
650 4 $a Molecular biology. $3 517296
650 4 $a Cellular biology. $3 3172791
650 4 $a Physiology. $3 518431
653 $a Endoplasmic reticulum
653 $a Phospholamban
653 $a Nucleotide
653 $a Lethal dilated cardiomyopathy
690 $a 0307
690 $a 0379
690 $a 0719
710 2 $a Loyola University Chicago. $b Physiology. $3 3771152
773 0 $t Dissertations Abstracts International $g 85-01B.
790 $a 0112
791 $a Ph.D.
792 $a 2023
793 $a English
856 4 0 $u https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30567382