Calcium Channel Research Group (Head: J. Striessnig)

 

 

Staff

 

Scientists:
- Nadja Hofer
- Nadine Ortner
- Anita Siller
- Jörg Striessnig
- Petronel Tuluc

Internal Collaborators:
- Nicolas Singewald
- Alexandra Koschak

 

Research in this group involves three major topics:

1. Physiology, pharmacology and pharmacotherapeutic potential of L - type calcium channels
2. Role of Cav1.3, Cav1.4 and Cav2.1 channels in human calcium channel diseases (channelopathies)
3. Funtional L-type calcium channel heterogeneity generated by alternative splicing

Are you familiar with voltage - gated ion channels in general and voltage - gated calcium channels in particular? If not, get a brief introduction here. 

1. Physiology, pharmacology and pharmacotherapeutic potential of L - type calcium channels
We study the physiological role and the biophysical properties in particular of Cav1.2 and Cav1.3 L-type calcium channels. These are the main isoforms expressed in the brain as well as in heart and endocrine cells. They can be distinguished with respect to their biophysical properties and tissue expression profile. Interestingly, the biophysical properties of Cav1.3 allow it to serve pacemaker functions in brain and heart. The effects of alternative splicing on channel function, its modulation by neurotransmitters, enzymes and drugs and its expression in different tissues are studied. We successfully generated Cav1.3 knockout and knockin mutant mice to dissect the physiological roles of these channels. In addition, we are currently identifying proteins associated with channel complexes which may participate in calcium channel signal transduction and channel fine - tuning. Our approach involves a combination of electrophysiological, molecular biological, cell biological techniques and behavioural experiments.
 
Selected references

Platzer J, Engel J, Schrott-Fischer A, Stephan K, Bova S, Chen H, Zheng H, Striessnig J (2000) "Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type calcium channels"
Cell 102: 89-97

Kraus RL, Hering S, Grabner M, Ostler D, Striessnig J (1998) "Molecular mechanisms of diltiazem interaction with L-type calcium channels" J Biol Chem 273: 27205-27212

Striessnig J, Grabner M, Mitterdorfer J, Hering S, Sinnegger MJ, Glossmann H (1998) "Structural basis of drug binding to L-type calcium channels" Trends Pharmacol Sci 19: 108-115

Koschak A, Reimer D, Huber IG, Grabner M, Glossmann H, Engel J, Striessnig J (2001) "α1D (Cav1.3) subunits can form L - type calcium channels activating at negative voltages" J Biol Chem 276: 22100-22106

Koschak A, Reimer D, Walter D, Hoda JC, Heinzle T, Grabner M, Striessnig J (2003) "Cav1.4α1 subunits can form slowly inactivating dihydropyridine - sensitive L-type calcium channels lacking calcium - dependent inactivation" J Neurosci: 23: 6041-6049

Sinnegger - Brauns MJ, Hetzenauer A, Huber IG, Renstrom E, Wietzorrek G, Berjukov S, Cavalli M, Walter D, Koschak A, Waldschutz R, Hering S, Bova S, Rorsman P, Pongs O, Singewald N, Striessnig J (2004) "Isoform - specific regulation of mood behavior and pancreatic β cell and cardiovascular function by L - type Ca2+ channels" J Clin Invest 113: 1430-9

Busquet P, Hetzenauer A, Sinnegger - Brauns MJ, Striessnig J, Singewald N (2008) "Role of L - type Ca2+ channel isoforms in the extinction of conditioned fear" Learn Mem 15: 378-86

Striessnig J, Koschak A (2008) "Exploring the function and pharmacotherapeutic potential of voltage-gated calcium channels with gene knockout models" Channels (Austin) 2:233-51

Sinnegger - Brauns MJ, Huber IG, Koschak A, Wild C, Obermair GJ, Einzinger U, Hoda JC, Sartori SB, Striessnig J (2008) "Expression and 1,4 - dihydropyridine-binding properties of brain L - type calcium channel isoforms" Mol Pharmacol 75: 407-414

Busquet P, Khoi Nguyen N, Schmid E, Tanimoto N, Seeliger MW, Ben - Yosef T, Mizuno F, Akopian A, Striessnig J, Singewald N "CaV1.3 L - type calcium channels modulate depression - like behaviour in mice independent of deaf phenotype" Int J Neuropsychopharmacol 13: 499-513

Marcantoni A, Vandael DH, Mahapatra S, Carabelli V, Sinnegger-Brauns MJ, Striessnig J, Carbone E (2010) "Loss of Cav1.3 channels reveals the critical role of L-type and BK channel coupling in pacemaking mouse adrenal chromaffin cells" J Neurosci 30:491-504

Schierberl K, Hao J, Tropea TF, Ra S, Giordano TP, Xu Q, Garraway SM, Hofmann F, Moosmang S, Striessnig J, Inturrisi CE, Rajadhyaksha AM (2011) "Cav1.2 L-type calcium channels mediate cocaine-Induced GluA1 trafficking in the nucleus accumbens, a long-term adaptation dependent on ventral tegmental area Cav1.3 channels" J Neurosci 31:13562-13575

Dragicevic E, Poetschke C, Duda J, Schlaudraff F, Lammel S, Schiemann J, Fauler M, Hetzel A, Watanabe M, Lujan R, Malenka RC, Striessnig J, Liss B (2014) "Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons" Brain, June 2014; doi: 10.1093/brain/awu131

Striessnig J, Pinggera A, Kaur G, Bock G, Tuluc P (2014) "L-type calcium channels in heart and brain" WIREs Membr Transp Signal doi: 10.1002/wmts.102

2. Role of Cav1.3, Cav1.4 and Cav2.1 channels in human calcium channel diseases (channelopathies)
We study the functional consequences of disease-related mutations within the pore-forming subunits of Cav1.3, Cav1.4 or Cav2.1 subunits. Such mutations were found in patients with a rare form of migraine (Cav2.1, Familial Hemiplegic Migraine) or Congenital Stationary Night Blindness Type 2 (Cav1.4, CSNB2). From this work we expect clues for a more complete understanding of the role of these calcium channels in neurons (Cav2.1, pathophysiology of migraine) or the retina (Cav1.4). Moreover, such human mutations reveal interesting insight into the structure-function relationship of calcium channels because most mutations cause changes in channel gating or channel surface expression. For example, a CSNB2 mutation in the C-terminal tail has recently led to the discovery of a novel C-terminal regulatory mechanism in Cav1.4 and Cav1.3 channels. The methods involve a combination of electrophysiological, molecular biological and cell biological techniques.
Our recent focus is on Cav1.3 channelopathies. We discovered a human channelopathy resulting from a loss-of-function mutation in the Cav1.3 (CACNA1D) gene (SANDD, Sinoatrial Node Dysfunction and Deafness) wich led to important insight into the role of Cav1.3 for human physiology and provided unexpected insight into the gating machinery of these channels. We also described somatic CACNA1D gain of function mutations associated with enhanced aldosterone production in aldosterone-producing adenomas
Selected references

Kraus RL, Sinnegger MJ, Glossmann H, Hering S, Striessnig J (1998) "Familial hemiplegic migraine mutations change α1A calcium channel kinetics" J Biol Chem 273: 5586-5590

Kraus RL, Sinnegger MJ, Glossmann H, Hering S, Striessnig J (1998) "Three new familial hemiplegic migraine mutants affect P/Q - type calcium channel kinetics" J Biol Chem 273: 5586-5590

Wappl E, Koschak A, Poteser M, Sinnegger MJ, Walter D, Eberhart A, Groschner K, Glossmann H, Kraus RL, Grabner M, Striessnig (2002) "Functional consequences of P/Q - type calcium channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia" J Biol Chem 277: 6960-6966

Pietrobon D, Striessnig J (2003) "Neurobiology of migraine" Nat Rev Neurosci 4: 386-398

Muellner C, Broos LA, van den Maagdenberg AM, Striessnig J (2004) "Familial hemiplegic migraine type 1 mutations K1336E, W1684R, and V1696I alter Cav2.1 calcium channel gating: evidence for β - subunit isoform - specific effects" J Biol Chem 279: 51844-51850

Singh A, Hamedinger D, Hoda JC, Gebhart M, Koschak A, Romanin C, Striessnig J (2006) "C - terminal modulator controls Ca2+ - dependent gating of Cav1.4 L - type calcium channels" Nat Neurosci 9: 1108-1116

Baig SM, Koschak A, Lieb A, Gebhart M, Dafinger C, Nurnberg G, Ali A, Ahmad I, Sinnegger-Brauns MJ, Brandt N, Engel J, Mangoni ME, Farooq M, Khan HU, Nurnberg P, Striessnig J, Bolz HJ (2011) "Loss of Cav1.3 (CACNA1D) function in a human channelopathy with bradycardia and congenital deafness" Nat Neurosci 14:77-84

Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, Maniero C, Garg S, Bochuko-va EG, Zhao W, Shaikh LH, Brighton CA, Teo AE, Davenport AP, Dekkers T, Tops B, Kusters B, Ceral J, Yeo GS, Neogi SG, McFarlane I, Rosenfeld N, Marass F, Hadfield J, Margas W, Chaggar K, Solar M, Deinum J, Dolphin AC, Farooqi IS, Striessnig J, Nissen P, Brown MJ (2013) "Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension." Nat Genet 45: 1055-1060

3. Functional L-type calcium channel heterogeneity generated by alternative splicing
We recently discovered a novel C - terminal regulatory mechanism in Cav1.3 and Cav1.4 channels. Interestingly, this mechanism is absent in a naturally occuring Cav1.3 splice variant generating a channel with faster inactivation and a more negative activation range. This project addresses the important question about the physiological significance of this splice variant and tries to identify other C - terminal splice variants with different gating behavior. We now generated a knockin mouse model in which inactivated this regulation. This now allows us to study its physiological. We assume that this will cause more overall channel activity. It is therefore possible that the C-terminal regulation modertaes Cav1.3 channel function in certain cells thus preventing cellular dysfunction resulting form exaggerated channel function. The methods involve a combination of electrophysiological, molecular biological, gene-targeting and cell biological techniques.
Selected references

Singh A, Hamedinger D, Hoda JC, Gebhart M, Koschak A, Romanin C, Striessnig J (2006) "C - terminal modulator controls Ca2+ - dependent gating of Cav1.4 L - type Ca2+ channels" Nat Neurosci 9: 1108-1116

Sinnegger - Brauns MJ, Huber IG, Koschak A, Wild C, Obermair GJ, Einzinger U, Hoda JC, Sartori SB, Striessnig J (2008) "Expression and 1,4 - dihydropyridine - binding properties of brain L - type calcium channel isoforms" Mol Pharmacol 75: 407-14

Singh A, Gebhart M, Fritsch R, Sinnegger - Brauns MJ, Poggiani C, Hoda JC, Engel J, Romanin C, Striessnig J, Koschak A (2008) "Modulation of voltage- and calcium - dependent gating of Cav1.3 L - type calcium channels by alternative splicing of a C - terminal regulatory domain" J Biol Chem 283: 20733-44

Striessnig J (2007) "C - terminal tailoring of L - type calcium channel function" J Physiol 585: 643-4

Bock G, Gebhart M, Scharinger A, Jangsangthong W, Busquet P, Poggiani C, Sartori S, Mangoni ME, Sinnegger-Brauns MJ, Herzig S, Striessnig J, Koschak A (2011) "Functional properties of a newly identified C-terminal splice variant of Cav1.3 L-type calcium channels" J Biol Chem 286:42736-48.

Lieb A, Ortner N, Striessnig J (2014) "C-terminal modulatory domain controls coupling of voltage-sensing to pore opening in Cav1.3 L-type calcium channels." Biophysical J 106: 1467-1475

 

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