| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
PERSPECTIVES |
1 Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria Email: joerg.striessnig{at}uibk.ac.at
Voltage-gated L-type (Cav1) Ca2+ channels are the well-known pharmacotherapeutic targets of Ca2+ channel blockers, such as dihydropyridines. Unlike what is expected from the selective effects of these drugs in heart and (vascular) smooth muscle L-type Ca2+ channels (LTCCs) are also expressed in skeletal muscle, endocrine tissues, sensory cells and neurons. Thus they serve as key signalling molecules for excitation–contraction coupling in skeletal muscle, stimulus–secretion coupling in endocrine tissues, sensory cell signalling, pacemaking in neurons and sinoatrial node and for neuronal plasticity. To adapt channel function to these different physiological needs, four pore-forming LTCC 
1-subunits (Cav1.1, Cav1.2, Cav1.3, Cav1.4) with unique functional properties evolved. Tight conformational coupling to ryanodine receptors makes Cav1.1 channels perfect voltage sensors for intracellular Ca2+ release in skeletal muscle; activation at relatively low voltages enables Cav1.3 Ca2+ currents (ICa) to support pacemaking activity in sinoatrial node (SAN) and some neurons, and very slow inactivation of Cav1.4 currents strengthens synaptic efficacy in retinal ribbon synapses.
However, this structural diversity is still not sufficient to fine-tune LTCC function to specific cellular functions. A well documented example exists for Cav1.3 channels: Cav1.3 ICa inactivates rapidly in SAN cells (Mangoni et al. 2003) where the transient inward current is suitable to support diastolic depolarization between two action potentials. In contrast, almost no inactivation occurs in cochlear inner hair cells (IHCs) (Platzer et al. 2000) where sound stimuli induce graded and tonic presynaptic depolarization and make neurotransmitter release dependent on sustained activation of presynaptic Cav1.3 channels.
The article by Cui et al. (2007) in this issue of The Journal of Physiology adds valuable information to a series of recent reports illustrating that sustained LTCC currents, as required in IHCs (Cav1.3) and retinal neurons (Cav1.4), are generated by switching off so-called Ca2+-dependent inactivation (CDI), an important negative feedback mechanism also found in other voltage-gated Ca2+ channel families. Ca2+ ions entering through Cav1.3 (or Cav1.2) channels can activate calmodulin (CaM), which is prebound to cytoplasmic regions (particularly an ‘IQ-domain’, Fig. 1
) within the proximal C-terminal tail of 1-subunits. Upon activation CaM introduces conformational changes which promote inactivation of the channels.
|
The relevance of CDI as a modulatory target is evident from the fact that CaBP-mediated control of LTCC inactivation represents only one of several different molecular mechanisms (Fig. 1) known to switch off CDI. Outer hair cells (OHCs) express a short Cav1.3 1-subunit splice variant that lacks the IQ domain as major CaM interaction site and therefore also CDI (Ihara et al. 1995; Shen et al. 2006). An even more complex mechanism was discovered for retinal Cav1.4 1. Although these subunits are principally capable of CaM-dependent CDI, it is completely prevented by a modulatory domain located within the distal C-terminus through its binding to upstream CaM interaction domains (Singh et al. 2006; Wahl-Schott et al. 2006).
Given this multitude of mechanisms moderating CDI, the paper by Cui et al. leaves us with an important question: Does CaBP1 account for most of the inhibition of CDI in IHCs or are multiple mechanisms involved? This question can only be addressed by targeted CaBP1 knockdown or knockout in future experiments.
References
Cui G, Meyer AC, Calin-Jageman I, Neef J, Haeseleer F, Moser T & Lee A (2007). J Physiol 585, 791–803.
Ihara Y, Yamada Y, Fujii Y, Gonoi T, Yano H, Yasuda K, Inagaki N, Seino Y & Seino S (1995). Mol Endocrinol 9, 121–130.[Abstract]
Mangoni ME, Couette B, Bourinet E, Platzer J, Reimer D, Striessnig J & Nargeot J (2003). Proc Natl Acad Sci U S A 100, 5543–5548.
Platzer J, Engel J, Schrott-Fischer A, Stephan K, Bova S, Chen H, Zheng H & Striessnig J (2000). Cell 102, 89–97.[CrossRef][Medline]
Shen Y, Yu D, Hiel H, Liao P, Yue DT, Fuchs PA & Soong TW (2006). J Neurosci 26, 10690–10699.
Singh A, Hamedinger D, Hoda JC, Gebhart M, Koschak A, Romanin C & Striessnig J (2006). Nat Neurosci 9, 1108–1116.[CrossRef][Medline]
Wahl-Schott C, Baumann L, Cuny H, Eckert C, Griessmeier K & Biel M (2006). Proc Natl Acad Sci U S A 103, 15657–15662.
Yang PS, Alseikhan BA, Hiel H, Grant L, Mori MX, Yang W, Fuchs PA & Yue DT (2006). J Neurosci 26, 10677–10689.
Zeitz C, Kloeckener-Gruissem B, Forster U, Kohl S, Magyar I, Wissinger B, Matyas G, Borruat FX, Schorderet DF, Zrenner E, Munier FL & Berger W (2006). Am J Hum Genet 79, 657–667.[CrossRef][Medline]
Zhou H, Kim SA, Kirk EA, Tippens AL, Sun H, Haeseleer F & Lee A (2004). J Neurosci 24, 4698–4708.
This article has been cited by other articles:
|
|
 |
|
  A. Singh, M. Gebhart, R. Fritsch, M. J. Sinnegger-Brauns, C. Poggiani, J.-C. Hoda, J. Engel, C. Romanin, J. Striessnig, and A. Koschak Modulation of Voltage- and Ca2+-dependent Gating of CaV1.3 L-type Calcium Channels by Alternative Splicing of a C-terminal Regulatory Domain J. Biol. Chem., July 25, 2008; 283(30): 20733 - 20744. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
