CACNA1D Membrane Protein Introduction

Introduction of CACNA1D

CACNA1D, Calcium channel, voltage-dependent, L type, alpha 1D subunit (also known as Ca_v1.3) is a protein that in humans is encoded by the CACNA1D gene. Ca_v1.3 channel is a member of the Ca_v1 family, which form L-type calcium currents and is sensitive to selective inhibition by dihydropyridines (DHP). It mediates the entry of calcium ions into excitable cells and is also involved in a variety of calcium-dependent processes, including muscle contraction, neurotransmitter or hormone release, gene expression, cell division cell motility, and cell death.

Function of CACNA1D Membrane Protein

CACNA1D is a member of voltage-sensitive calcium channels (VSCC) which mediates the entry of calcium ions into excitable cells and is also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division, and cell death. The isoform alpha-1D gives rise to L-type calcium currents. It has been identified that Long-lasting (L-type) calcium channels are members of the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin-GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA).

Fig.1 Ca_v1.3 isoform structure. (Zuccotti, 2011)

Application of CACNA1D Membrane Protein in Literature

1. Azizan E.A., et al. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet. 2013, 45(9): 1055-60. PubMed ID: 23913004
   
   

   This article found that mutations of CACNA1D ATP1A1 and caused a shift of voltage-dependent gating to more negative voltages, suppressed inactivation or increased currents. Identification of the distinct genotype and phenotype for this subset could facilitate diagnosis.

2. Tan G.C., et al. Aldosterone-Producing Adenomas: Histopathology-Genotype Correlation and Identification of a Novel CACNA1D Mutation. Hypertension. 2017, 70(1): 129-136. PubMed ID: 28584016
   
   

   This article found that the mutation in CACNA1D caused a hyperpolarizing shift of the voltage-dependent inactivation and activation and slowed the channel's inactivation kinetics. ATP1A1 and CACNA1D mutant adenomas had a specific histopathologic phenotype.

3. Kabir Z.D., et al. From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms. Neurotherapeutics. 2017, 14(3): 588-613. PubMed ID: 28497380
   
   

   This study provided an overview of clinical studies that had evaluated LTCC blockers for BD, SCZ, and drug dependence-associated symptoms, in addition, rodent studies that had identified Ca_v1.2 and Ca_v1.3 specific molecular and cellular cascades that underlie mood (anxiety, depression), social behavior, cognition, and addiction.

4. Pinggera A., et al. New gain-of-function mutation shows CACNA1D as recurrently mutated gene in autism spectrum disorders and epilepsy. Hum Mol Genet. 2017, 26(15): 2923-2932. PubMed ID: 28472301
   
   

   This article proved that CACNA1D could be as a new candidate autism risk gene and encouraged experimental therapy with available channel-blockers for this mutation. The additional presence of seizures and neurological abnormalities in our patient defined a novel phenotype partially overlapping with symptoms in two individuals with PASNA (congenital primary aldosteronism, seizures, and neurological abnormalities) caused by similar Ca_v1.3 gain-of-function mutations.

5. Vincent P.F., et al. Different Ca_V1.3 Channel Isoforms Control Distinct Components of the Synaptic Vesicle Cycle in Auditory Inner Hair Cells. J Neurosci. 2017, 37(11): 2960-2975. PubMed ID: 28193694
   
   

   This article showed that this synaptic process involved long and short C-terminal isoforms of the Ca_v1.3 Ca²⁺ channel that differed in the kinetics of their Ca²⁺-dependent inactivation and their relative sensitivity to the L-type Ca²⁺ channel blocker nifedipine. The long isoforms, with slow inactivation and great sensitivity to nifedipine, mainly regulated the vesicular replenishment of the RRP; that was, the sustained or tonic exocytosis.

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Reference

1. Zuccotti A, et al. (2011). Structural and functional differences between L-type calcium channels: crucial issues for future selective targeting. Trends Pharmacol Sci. 32(6):366-75.

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