Disease relevance of CACNA1D

• In addition, the PCR-SSCP procedure of exon 1 of CACNL1A2 revealed a change from 7 to 8 ATG trinucleotide repeats in a patient with non-insulin-dependent diabetes mellitus (NIDDM), resulting in an addition of methionine at the amino-terminus of CACN4 [1].
• In this study we have isolated complementary DNAs encoding two forms of rat CACN4 (rCACN4A and rCACN4B) from a rat insulinoma RINm5F complementary DNA library [2].
• Studies of animal models with chronic hyperglycemia and starvation have indicated that the reduced CACN4 mRNA levels in pancreatic islets are associated with impaired insulin responses to stimuli in both hyperglycemic and fasting states [3].

High impact information on CACNA1D

• We recently have cloned a human alpha 1-subunit of the VDCC expressed in pancreatic beta-cells, designated CACN4 [2].
• Rat CACN4A is a protein of 2203 amino acids and is the rat homolog of human CACN4, whereas rCACN4B lacks 535 amino acids in the carboxyl-terminal region, probably due to alternative splicing [2].
• The alpha 1 subunit (CACN4) and the beta subunit (beta 3) of VDCCs, both of which are expressed in pancreatic islets, are major components for the VDCC activity, and so they may play a critical role in the regulation of insulin secretion [1].
• The CACNL1A2 gene spans more than 155 kb and has 49 exons [1].
• Assignment of the gene encoding the alpha 1 subunit of the neuroendocrine/brain-type calcium channel (CACNL1A2) to human chromosome 3, band p14.3 [4].

Biological context of CACNA1D

• The evolutionary conservation of this gene cluster includes three adjacent human shortest regions of overlap (SROs): 3p21.1 (ACY1), 3p21.3-->p21.2 (CACNA1D), and 3p21.3 (ZNF64) [5].
• Similarly, segregation among human X rodent somatic cell hybrids indicated that CCHL1A2 maps to human chromosome 3 [6].
• A brain L-type calcium channel alpha 1 subunit gene (CCHL1A2) maps to mouse chromosome 14 and human chromosome 3 [6].
• Molecular cloning of a novel alpha 1 subunit (beta-cell/neuroendocrine type, CACN4) of VDCCs from pancreatic islets and insulinoma have made it possible to study the electrophysiological and pharmacogical properties, regulation, and genetics of the VDCCs expressed in beta-cells [3].

Anatomical context of CACNA1D

• Molecular diversity and functional characterization of voltage-dependent calcium channels (CACN4) expressed in pancreatic beta-cells [2].
• The CACN4 is structurally related to other members of the VDCC alpha 1 subunit family, including skeletal muscle, cardiac, and brain types [3].

Analytical, diagnostic and therapeutic context of CACNA1D

• In situ hybridization experiments reveal that CACN4 mRNAs are expressed in beta-cells in the islets [3].

References