Engineering proteins for custom inhibition of Ca(V) channels.
The influx of Ca(2+) ions through voltage-dependent calcium (Ca(V)) channels links electrical signals to physiological responses in all excitable cells. Not surprisingly, blocking Ca(V) channel activity is a powerful method to regulate the function of excitable cells, and this is exploited for both physiological and therapeutic benefit. Nevertheless, the full potential for Ca(V) channel inhibition is not being realized by currently available small-molecule blockers or second-messenger modulators due to limitations in targeting them either to defined groups of cells in an organism or to distinct subcellular regions within a single cell. Here, we review early efforts to engineer protein molecule blockers of Ca(V) channels to fill this crucial niche. This technology would greatly expand the toolbox available to physiologists studying the biology of excitable cells at the cellular and systems level.
Xu
Xianghua
X
Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Colecraft
Henry M
HM
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009206:Myocardium / Q000166:cytology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D015202:Protein Engineering / Q000379:methods*
D002121:Calcium Channel Blockers; D015220:Calcium Channels
Structure. 2008 Oct 8;16(10):1455-67
18940602
Nature. 2004 Jun 10;429(6992):675-80
15170217
Biochem Pharmacol. 2007 Jun 30;74(1):1-9
17276408
Neuron. 2007 Apr 5;54(1):35-49
17408576
Annu Rev Biochem. 1994;63:823-67
7979255
J Biol Chem. 1997 Aug 29;272(35):21982-8
9268335
Nat Med. 2000 Dec;6(12):1395-8
11100126
J Neurosci. 1999 Jan 15;19(2):684-91
9880589
Med Res Rev. 1999 Mar;19(2):149-77
10189176
J Gen Physiol. 2009 Mar;133(3):327-43
19237593
FEBS Lett. 1991 Oct 21;291(2):253-8
1657644
Science. 1995 May 19;268(5213):1045-9
7754384
J Neurosci. 2004 Sep 29;24(39):8494-9
15456823
J Biol Chem. 1997 Jul 25;272(30):18759-65
9228049
Pflugers Arch. 1989 Jun;414(2):150-6
2547195
J Neurosci. 1999 Mar 1;19(5):1691-7
10024355
Pain. 2006 Nov;125(1-2):20-34
16764990
Science. 1994 Apr 1;264(5155):107-11
7832825
Nature. 1999 May 13;399(6732):155-9
10335845
Curr Biol. 1996 Apr 1;6(4):382-4
8723338
J Biol Chem. 1992 Jan 25;267(3):1792-7
1370480
Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14469-74
14623965
PLoS One. 2008;3(10):e3560
18958281
Am J Physiol. 1983 Jul;245(1):C1-14
6346892
Neuron. 1999 Mar;22(3):549-58
10197534
J Biol Chem. 2003 Jun 13;278(24):21315-8
12676943
Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17537-42
17088553
Nature. 2001 Jun 7;411(6838):701-6
11395774
Biophys J. 1992 Aug;63(2):497-517
1330031
Nature. 1992 Feb 27;355(6363):827-9
1311418
Cell Calcium. 2006 Aug;40(2):97-114
16777221
Biochem J. 2000 Apr 1;347 Pt 1:223-31
10727423
Neuron. 1994 Dec;13(6):1433-8
7993634
Neuron. 2007 Jan 18;53(2):217-32
17224404
Neuron. 2005 Dec 8;48(5):727-35
16337911
J Gen Physiol. 1998 Aug;112(2):125-43
9689023
Science. 2006 Dec 1;314(5804):1458-61
17095657
J Cell Biol. 1995 May;129(3):673-82
7730403
Annu Rev Biochem. 2005;74:219-45
15952887
Neuron. 1989 May;2(5):1453-63
2560643
J Gen Physiol. 2000 Feb;115(2):175-92
10653895
EMBO J. 1996 May 15;15(10):2365-70
8665843
Nature. 1996 Mar 21;380(6571):255-8
8637575
J Neurosci. 1997 Sep 15;17(18):6884-91
9278523
Nature. 1996 Oct 3;383(6599):431-4
8837774
Nat Chem Biol. 2007 Dec;3(12):795-804
17952065
J Biol Chem. 1996 Mar 8;271(10):5293-6
8621376
J Biol Chem. 2006 Aug 18;281(33):23557-66
16790445
J Neurosci. 2001 Aug 15;21(16):5944-51
11487617
J Mol Biol. 2006 Jan 6;355(1):34-46
16298391
J Biol Chem. 1993 Jun 15;268(17):12359-66
7685340
J Biol Chem. 2006 Jan 20;281(3):1827-39
16293615
Annu Rev Cell Dev Biol. 2000;16:521-55
11031246
Trends Neurosci. 1988 Oct;11(10):425-30
2469159
Biochem J. 2005 Aug 15;390(Pt 1):67-75
15862114
Nature. 1994 Mar 3;368(6466):67-70
7509046
Proc Natl Acad Sci U S A. 2006 May 9;103(19):7500-5
16648270
Neuron. 2004 May 13;42(3):387-99
15134636
Science. 1993 Nov 26;262(5138):1441-4
8248782
Sci STKE. 2004 Sep 07;2004(250):RE13
15367757
J Neurosci. 2007 Aug 22;27(34):9086-93
17715345
Circ Res. 1999 Oct 29;85(9):770-6
10532944
Nature. 2002 Jan 10;415(6868):219-26
11805846
J Bioenerg Biomembr. 2003 Dec;35(6):477-89
15000517
J Neurosci. 2005 Oct 19;25(42):9762-72
16237180
Circulation. 2007 Dec 18;116(25):2976-2983
18056528
J Biol Chem. 2003 Dec 26;278(52):52323-32
14559910
Mol Pharmacol. 2002 Sep;62(3):485-96
12181424
J Clin Invest. 2006 Mar;116(3):623-6
16511595
J Physiol. 2002 Jun 1;541(Pt 2):435-52
12042350
Biochemistry. 1998 Nov 3;37(44):15353-62
9799496
Trends Neurosci. 2006 Nov;29(11):617-24
16942804
Neuron. 2004 Aug 5;43(3):305-11
15294139
J Cell Biol. 1995 May;129(3):659-71
7730402
Nat Methods. 2005 Jun;2(6):415-8
15908919
Cell Calcium. 2003 Mar;33(3):145-62
12600802
J Neurosci. 2004 Oct 6;24(40):8818-22
15470147
Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5163-8
17360345
J Bioenerg Biomembr. 2003 Dec;35(6):599-620
15000522
J Physiol. 1967 Nov;193(2):419-32
6065887
J Biol Chem. 2007 Apr 13;282(15):11509-20
17303572
J Biol Chem. 1996 Mar 8;271(10):5768-76
8621444
Nature. 2004 Jun 10;429(6992):671-5
15141227
Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3628-33
18299583
Biophys J. 2000 Nov;79(5):2682-91
11053140
Nature. 1989 Jul 13;340(6229):153-6
2567963
Nat Neurosci. 2006 Jan;9(1):31-40
16311589
Circ Res. 2004 Aug 20;95(4):398-405
15242970
Science. 1991 Sep 27;253(5027):1553-7
1716787
CNS Neurol Disord Drug Targets. 2006 Dec;5(6):605-9
17168745
J Biol Chem. 1991 Feb 15;266(5):3287-93
1847144
Neuron. 2008 Sep 25;59(6):873-81
18817728
J Mol Cell Cardiol. 2000 Nov;32(11):1981-94
11040103
Nat Struct Mol Biol. 2005 Dec;12(12):1108-15
16299511
Trends Biochem Sci. 1996 Nov;21(11):418-22
8987395
Nature. 1996 Mar 21;380(6571):258-62
8637576
Pflugers Arch. 1994 Oct;428(5-6):499-507
7838672
J Physiol. 1995 Nov 15;489 ( Pt 1):55-62
8583415
Science. 1994 Jul 8;265(5169):241-4
7912851
Nature. 1998 Oct 29;395(6705):900-5
9804423
J Biol Chem. 2000 Apr 21;275(16):12237-42
10766861
Proc Natl Acad Sci U S A. 2006 May 16;103(20):7535-6
16682624
J Neurosci. 2000 Jan 1;20(1):171-8
10627594
Nature. 1978 Dec 21-28;276(5690):837-9
31570
J Biol Chem. 2005 Dec 23;280(51):41864-71
15728182
Biophys J. 2003 May;84(5):3007-21
12719232
J Cell Sci. 2005 May 1;118(Pt 9):1923-34
15860732
J Biol Chem. 1993 Feb 15;268(5):3450-5
7679112
Nature. 2007 Apr 5;446(7136):633-9
17410168
Neuron. 1990 Jul;5(1):75-80
2164405
Toxicon. 1997 Aug;35(8):1161-91
9278968
Nature. 1991 Aug 8;352(6335):527-30
1650913
Structure. 2008 Apr;16(4):607-20
18400181
J Physiol. 1995 Jun 15;485 ( Pt 3):619-34
7562605
Trends Pharmacol Sci. 1998 Mar;19(3):108-15
9584627
Neuron. 1996 Jan;16(1):207-18
8562085
Science. 1988 Sep 23;241(4873):1661-4
2458626
Nature. 1999 May 13;399(6732):159-62
10335846
Physiol Rev. 2003 Jan;83(1):117-61
12506128
J Neurophysiol. 2004 Nov;92(5):2633-41
15486420
Neuron. 2008 Mar 13;57(5):634-60
18341986
Science. 1989 Sep 8;245(4922):1115-8
2549640
Neuron. 2008 Sep 25;59(6):882-901
18817729
Cell Signal. 2008 Feb;20(2):292-300
18042346
Curr Opin Pharmacol. 2001 Feb;1(1):11-6
11712528
Handb Exp Pharmacol. 2008;(184):45-75
18064411