Gerhard Meissner, PhD
Professor
Joint Appointment in the Department of Biochemistry and Biophysics

Education:

MD, Technical University Berlin, 1965

Structure and Regulation of Intracellular Calcium Channels

The goal of the laboratory’s research is to elucidate the molecular properties of the sarcoplasmic reticulum calcium-release channels of skeletal and cardiac muscle. Their major function is to release calcium from an intracellular calcium-storing compartment, the sarcoplasmic reticulum, in order to allow the contraction of muscle. Calcium-release from the sarcoplasmic reticulum is affected in response to a muscle action potential by a direct (skeletal muscle) or indirect (cardiac muscle) interaction of calcium-release channels with transverse tubular calcium channels (L-type). Relaxation of muscle is affected by a calcium pump, or calcium-ATPase, which transports the released calcium from the myofibrillar space back into the sarcoplasmic reticulum.

The calcium-release channels are also known as ryanodine receptors because they bind the plant alkaloid, ryanodine, with high affinity and specificity. They have been purified as 30S protein complexes comprised of four large (ryanodine receptor, Mr ~560,000) and four small (FK506 binding protein, Mr 12,600) subunits, and shown to be regulated by endogenous effector molecules including calcium, magnesium, ATP, calmodulin, protein kinases, NO, and reactive oxygen intermediates. Two principal hypotheses being tested in the laboratory are that there are discrete regulatory domains, and that in fatigued and ischemic tissues, changes in the intracellular ionic milieu and the phosphorylation and redox states elicit changes in calcium release channel function. The laboratory addresses these hypotheses using biochemical, electrophysiological and molecular biological methods. Our reagents include isolated membrane and purified channel preparations, mutant proteins and knock-in mouse models.

Representative Publications

Yamaguchi N, Xu L, Evans KE, Pasek DA, Meissner G. (2004) Different regions in skeletal and cardiac muscle ryanodine receptors are involved in transducing the functional effects of calmodulin. J Biol Chem. 279(35):36433-9.

Meissner G. (2004) Molecular regulation of cardiac ryanodine receptor ion channel.
Cell Calcium. 35(6):621-8. Review

Meissner G. (2004) NADH, a new player in the cardiac ryanodine receptor?
Circ Res. 94(4):418-9.

Xu L, Meissner G. (2004) Mechanism of calmodulin inhibition of cardiac sarcoplasmic reticulum Ca2+ release channel (ryanodine receptor). Biophys J. 86(2):797-804.

Eu JP, Hare JM, Hess DT, Skaf M, Sun J, Cardenas-Navina I, Sun QA, Dewhirst M, Meissner G, Stamler JS. (2003) Concerted regulation of skeletal muscle contractility by oxygen tension and endogenous nitric oxide. Proc Natl Acad Sci U S A. 100(25):15229-34.

Matalon S, Hardiman KM, Jain L, Eaton DC, Kotlikoff M, Eu JP, Sun J, Meissner G, Stamler JS. (2003) Regulation of ion channel structure and function by reactive oxygen-nitrogen species.
Am J Physiol Lung Cell Mol Physiol.285(6):L1184-9. Review.

Stange M, Xu L, Balshaw D, Yamaguchi N, Meissner G. (2003) Characterization of recombinant skeletal muscle (Ser-2843) and cardiac muscle (Ser-2809) ryanodine receptor phosphorylation mutants. J Biol Chem. 278(51):51693-702.

Yamaguchi N, Xu L, Pasek DA, Evans KE, Meissner G. (2003) Molecular basis of calmodulin binding to cardiac muscle Ca(2+) release channel (ryanodine receptor). J Biol Chem. 278(26):23480-6.

Bidasee KR, Xu L, Meissner G, Besch HR Jr. (2003) Diketopyridylryanodine has three concentration-dependent effects on the cardiac calcium-release channel/ryanodine receptor.
J Biol Chem. 2003 278(16):14237-48.

Zorzato F, Yamaguchi N, Xu L, Meissner G, Muller CR, Pouliquin P, Muntoni F, Sewry C, Girard T, Treves S. (2003) Clinical and functional effects of a deletion in a COOH-terminal lumenal loop of the skeletal muscle ryanodine receptor. Hum Mol Genet.12(4):379-88.

Tijskens P, Meissner G, Franzini-Armstrong C. (2003) Location of ryanodine and dihydropyridine receptors in frog myocardium. Biophys J. 84(2 Pt 1):1079-92.

Sun J, Xu L, Eu JP, Stamler JS, Meissner G. (2003) Nitric oxide, NOC-12, and S-nitrosoglutathione modulate the skeletal muscle calcium release channel/ryanodine receptor by different mechanisms. An allosteric function for O2 in S-nitrosylation of the channel.
J Biol Chem. 278(10):8184-9.

Meissner G. (2002) Regulation of mammalian ryanodine receptors. Front Biosci. 2002 7:d2072-80. Review.

O'Connell KM, Yamaguchi N, Meissner G, Dirksen RT. (2002) Calmodulin binding to the 3614-3643 region of RyR1 is not essential for excitation-contraction coupling in skeletal myotubes.
J Gen Physiol. 120(3):337-47.

Wang SQ, Song LS, Xu L, Meissner G, Lakatta EG, Rios E, Stern MD, Cheng H. (2002) Thermodynamically irreversible gating of ryanodine receptors in situ revealed by stereotyped duration of release in Ca(2+) sparks. Biophys J. 83(1):242-51.

Lee EH, Meissner G, Kim do H. (2002) Effects of quercetin on single Ca(2+) release channel behavior of skeletal muscle. Biophys J. 82(3):1266-77.

Balshaw DM, Yamaguchi N, Meissner G. (2002) Modulation of intracellular calcium-release channels by calmodulin. J Membr Biol.185(1):1-8.

Sun J, Xin C, Eu JP, Stamler JS, Meissner G. (2001) Protein Cysteine-3635 is responsible for skeletal muscle ryanodine receptor modulation by NO. Proc Natl Acad Sci U S A. 98(20):11158-62.

Stange M, Tripathy A, Meissner G. (2001) Two domains in dihydropyridine receptor activate the skeletal muscle Ca(2+) release channel. Biophys J. 81(3):1419-29

Balshaw DM, Xu L, Yamaguchi N, Pasek DA, Meissner G. (2001) Calmodulin binding and inhibition of cardiac muscle calcium release channel (ryanodine receptor). J Biol Chem. 276(23):20144-53

Yamaguchi N, Xin C, Meissner G. (2001) Identification of apocalmodulin and Ca2+-calmodulin regulatory domain in skeletal muscle Ca2+ release channel, ryanodine receptor.(2001) J Biol Chem 276(25):22579-85.

Sun J, Xu L, Eu JP, Stamler JS, Meissner G. (2001) Classes of thiols that influence the activity of the skeletal muscle calcium release channel. J Biol Chem. 276(19):15625-30

Protasi F, Takekura H, Wang Y, Chen SR, Meissner G, Allen PD, Franzini-Armstrong C. (2000) RYR1 and RYR3 have different roles in the assembly of calcium release units of skeletal muscle. Biophys J. 79(5): 2494-508.

Eu, J.P., Sun. J., Xu. L., Stamler. J.S., and Meissner, G. (2000). TThe skeletal muscle calcium release channel: coupled O2 sensor and NO signaling functions. Cell 102:499-509.

Gao, L., Balshaw, D., Xu, L., Tripathy. A., Xin, C., and Meissner, G. (2000). Evidence for a role of the lumenal M3-M4 loop in skeletal muscle Ca²⁺ release channel (ryanodine receptor) activity and conductance. Biophys. J 79:828-840.

Xu L, Tripathy A, Pasek DA, Meissner G. (1999) Ruthenium red modifies the cardiac and skeletal muscle Ca(2+) release channels (ryanodine receptors) by multiple mechanisms. J Biol Chem. 274(46):32680-91

Xiong, H., Feng, X., Gao, L., Xu, L., Pasek, D.A., Seok, J.H., and Meissner, G. (1998). Identification of a two EF-hand calcium binding domain in lobster skeletal muscle ryanodine receptor/calcium release channel. Biochemistry 37:4804-4814.

Xu, L. and Meissner, G. (1998). Regulation of cardiac muscle calcium release channel by sarcoplasmic reticulum lumenal calcium. Biophysics Journal 75:2302-2312.