Channelopathies in Cav1.1, Cav1.3, and Cav1.4 voltage-gated L-type Ca2+ channels

Voltage-gated Ca2+ channels couple membrane depolarization to Ca2+-dependent intracellular signaling events. This is achieved by mediating Ca2+ ion influx or by direct conformational coupling to intracellular Ca2+ release channels. The family of Cav1 channels, also termed L-type Ca2+ channels (LTCCs), is uniquely sensitive to organic Ca2+ channel blockers and expressed in many electrically excitable tissues. In this review, we summarize the role of LTCCs for human diseases caused by genetic Ca2+ channel defects (channelopathies). LTCC dysfunction can result from structural aberrations within their pore-forming α1 subunits causing hypokalemic periodic paralysis and malignant hyperthermia sensitivity (Cav1.1 α1), incomplete congenital stationary night blindness (CSNB2; Cav1.4 α1), and Timothy syndrome (Cav1.2 α1; reviewed separately in this issue). Cav1.3 α1 mutations have not been reported yet in humans, but channel loss of function would likely affect sinoatrial node function and hearing. Studies in mice revealed that LTCCs indirectly also contribute to neurological symptoms in Ca2+ channelopathies affecting non-LTCCs, such as Cav2.1 α1 in tottering mice. Ca2+ channelopathies provide exciting disease-related molecular detail that led to important novel insight not only into disease pathophysiology but also to mechanisms of channel function

A Folding Pathway-Dependent Score to Recognize Membrane Proteins

While various approaches exist to study protein localization, it is still a challenge to predict where proteins localize. Here, we consider a mechanistic viewpoint for membrane localization. Taking into account the steps for the folding pathway of α-helical membrane proteins and relating biophysical parameters to each of these steps, we create a score capable of predicting the propensity for membrane localization and call it FP3mem. This score is driven from the principal component analysis (PCA) of the biophysical parameters related to membrane localization. FP3mem allows us to rationalize the colocalization of a number of channel proteins with the Cav1.2 channel by their fewer propensities for membrane localization

Dissecting the functional role of different isoforms of the L-type Ca(2+) channel

There currently exist a great number of different mouse lines in which the activity of a particular gene of interest has been inactivated or enhanced. However, it is also possible to insert specific mutations in a gene so that the pharmacological sensitivity of the gene product is altered. An example of such an approach shows how the abolition of the sensitivity of an L-type Ca(2+) channel isoform to dihydropyridines allows the investigation of the physiological role of these channels in different tissues

Molecular nature of anomalous L-type calcium channels in mouse cerebellar granule cells.

Single-channel analysis revealed the existence of neuronal L-type Ca2+ channels (LTCCs) with fundamentally different gating properties; in addition to LTCCs resembling cardiac channels, LTCCs with anomalous gating were identified in a variety of neurons, including cerebellar granule cells. Anomalous LTCC gating is mainly characterized by long reopenings after repolarization following strong depolarizations or trains of action potentials. To elucidate the unknown molecular nature of anomalous LTCCs, we performed single-channel patch-clamp recordings from cerebellar granule cells of wild-type, Ca(v)1.3(-/-) and Ca(v)1.2DHP(-/-) [containing a mutation in the Ca(v)1.2 alpha(1) subunit that eliminates dihydropyridine (DHP) sensitivity] mice. Quantitative reverse transcription-PCR revealed that Ca(v)1.2 accounts for 89% and Ca(v)1.3 for 11% of the LTCC transcripts in wild- type cerebellar granule cells, whereas Ca(v)1.1 and Ca(v)1.4 are expressed at insignificant levels. Anomalous LTCCs were observed in neurons of Ca(v)1.3(-/-) mice with a frequency not different from wild type. In the presence of the DHP agonist (+)-( S)- 202- 791, the typical prepulse- induced reopenings of anomalous LTCCs after repolarization were shorter in Ca(v)1.2DHP(-/-) neurons than in Ca(v)1.3(-/-) neurons. Reopenings in Ca(v)1.2DHP(-/-) neurons in the presence of theDHPagonist were similar to those in wild- type neurons in the absence of the agonist. These data show that Ca(v)1.2 alpha(1) subunits are the pore- forming subunits of anomalous LTCCs in mouse cerebellar granule cells. Given the evidence that Ca(v)1.2 channels are specifically involved in sustained Ras- MAPK (mitogen-activated protein kinase)- dependent cAMP response element- binding protein phosphorylation and LTCC-dependent hippocampal long- term potentiation (LTP) ( Moosmang et al., 2005), we discuss the hypothesis that anomalous rather than cardiac-type Ca(v)1.2 channels are specifically involved in LTCC-dependent and gene transcription- dependent LTP