Ca2+ channels: diversity of form and function

doi:10.1016/0959-4388(92)90111-W

Current Opinion in Neurobiology

Volume 2, Issue 3, June 1992, Pages 247-253

https://doi.org/10.1016/0959-4388(92)90111-W Get rights and content

Abstract

The past year has seen some significant advances in our understanding of the structural and functional properties of neuronal voltage-gated Ca²⁺ channels. Molecular cloning and protein purification studies have identified structural components, and expression studies are beginning to define the biophysical and pharmacological properties of the cloned channels. A number of studies of native Ca²⁺ channels show that the concept of channel modulation includes gating by both voltage and ligands.

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CaV channels are generally categorized into two groups according to their activation threshold, i.e., high-voltage activated (HVA) and low-voltage activated (LVA) CaV channels. Based on their sequence homology, CaV channels in mammals contain 10 members, which are further classified into three subfamilies (CaV1, CaV2, and CaV3) that conduct six types of Ca2+ current (L-, P/Q-, N-, R-, T-types) (Catterall et al., 2005; Nowycky et al., 1985; Snutch and Reiner, 1992). CaV2.2 is a HVA channel that is exclusively expressed in central and peripheral neurons (Olivera et al., 1994).
N-type voltage-gated calcium (Ca_V) channels mediate Ca²⁺ influx at presynaptic terminals in response to action potentials and play vital roles in synaptogenesis, release of neurotransmitters, and nociceptive transmission. Here, we elucidate a cryo-electron microscopy (cryo-EM) structure of the human Ca_V2.2 complex in apo, ziconotide-bound, and two Ca_V2.2-specific pore blockers-bound states. The second voltage-sensing domain (VSD) is captured in a resting-state conformation, trapped by a phosphatidylinositol 4,5-bisphosphate (PIP₂) molecule, which is distinct from the other three VSDs of Ca_V2.2, as well as activated VSDs observed in previous structures of Ca_V channels. This structure reveals the molecular basis for the unique inactivation process of Ca_V2.2 channels, in which the intracellular gate formed by S6 helices is closed and a W-helix from the domain II–III linker stabilizes closed-state inactivation. The structures of this inactivated, drug-bound complex lay a solid foundation for developing new state-dependent blockers for treatment of chronic pain.
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Eukaryote voltage-gated Ca²⁺ channels of the Ca_V2 channel family are hetero-oligomers formed by the pore-forming Ca_Vα1 protein assembled with auxiliary Ca_Vα2δ and Ca_Vβ subunits. Ca_Vβ subunits are formed by a Src homology 3 (SH3) domain and a guanylate kinase (GK) domain connected through a HOOK domain. The GK domain binds a conserved cytoplasmic region of the pore-forming Ca_Vα1 subunit referred as the “AID”. Herein we explored the phylogenetic and functional relationship between Ca_V channel subunits in distant eukaryotic organisms by investigating the function of a MAGUK protein (XM_004990081) cloned from the choanoflagellate Salpingoeca rosetta (Sro). This MAGUK protein (Sroβ) features SH3 and GK structural domains with a 25% primary sequence identity to mammalian Ca_Vβ. Recombinant expression of its cDNA with mammalian high-voltage activated Ca²⁺ channel Ca_V2.3 in mammalian HEK cells produced robust voltage-gated inward Ca²⁺ currents with typical activation and inactivation properties. Like Ca_Vβ, Sroβ prevents fast degradation of total Ca_V2.3 proteins in cycloheximide assays. The three-dimensional homology model predicts an interaction between the GK domain of Sroβ and the AID motif of the pore-forming Ca_Vα1 protein. Substitution of AID residues Trp (W386A) and Tyr (Y383A) significantly impaired co-immunoprecipitation of Ca_V2.3 with Sroβ and functional upregulation of Ca_V2.3 currents. Likewise, a 6-residue deletion within the GK domain of Sroβ, similar to the locus found in mammalian Ca_Vβ, significantly reduced peak current density. Altogether our data demonstrate that an ancestor MAGUK protein reconstitutes the biophysical and molecular features responsible for channel upregulation by mammalian Ca_Vβ through a minimally conserved molecular interface.
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Citation Excerpt :
At the presynaptic terminal, neuronal firing activity induces membrane depolarization and subsequent Ca2+ entry through voltage-gated Ca2+ (CaV) channels triggers neurotransmitter release from the active zone (AZ). Multiple mechanisms directly or indirectly modulate the function of presynaptic Ca2+ channels (Catterall and Few, 2008; Dunlap et al., 1995; Snutch and Reiner, 1992; Tedford and Zamponi, 2006). The ability of CaV channels to open, close, or inactivate in response to membrane depolarization changes temporally during and after neuronal firing activity and alters efficacy of synaptic transmission (Catterall and Few, 2008; Tedford and Zamponi, 2006).
At the presynaptic terminal, neuronal firing activity induces membrane depolarization and subsequent Ca²⁺ entry through voltage-gated Ca²⁺ (Ca_V) channels triggers neurotransmitter release from the active zone. Presynaptic Ca²⁺ channels form a large signaling complex, which targets synaptic vesicles to Ca²⁺ channels for efficient release and mediates Ca²⁺ channel regulation. The presynaptic Ca_V2 channel family (comprising Ca_V2.1, Ca_V2.2 and Ca_V2.3 isoforms) encode the pore-forming α1 subunit. The cytoplasmic regions are the target of regulatory proteins for channel modulation. Modulation of presynaptic Ca²⁺ channels has a powerful influence on synaptic transmission. This article overviews spatial and temporal regulation of Ca²⁺ channels by effectors and sensors of Ca²⁺ signaling, and describes the emerging evidence for a critical role of Ca²⁺ channel regulation in control of synaptic transmission and presynaptic plasticity. Sympathetic superior cervical ganglion neurons in culture expressing Ca_V2.2 channels represent a well-characterized system for investigating synaptic transmission. The exogenously expressed α1 subunit of the Ca_V2.1 as well as endogenous Ca_V2.2 was examined for modulation of channel activity, and thereby regulation of synaptic transmission. The constitutive and Ca²⁺-dependent modulation of Ca_V2.1 channels coordinately act as spatial and temporal molecular switches to control synaptic efficacy.
Voltage-gated calcium channels: Determinants of channel function and modulation by inorganic cations
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Citation Excerpt :
Subsequent homology screening of lambda-phage and cDNA libraries revealed several additional genes encoding mammalian Ca2+ channel α1-subunits and firmly established that the functional diversity of native Ca2+ currents arises from multiple distinct types of VGCCs (Hille, 2001; Catterall, 2011). Their naming followed an alphabetical nomenclature, which assigned the letter S to the original skeletal muscle channel (i.e. α1S) and the letters A–F to subsequently identified α1-subunits (Snutch et al., 1990; Snutch and Reiner, 1992; Birnbaumer et al., 1994). It has since been superseded by a classification into three subfamilies based on amino acid sequence identity and the same numerical nomenclature used for other voltage-gated ion channels (Table 1).
Voltage-gated calcium channels (VGCCs) represent a key link between electrical signals and non-electrical processes, such as contraction, secretion and transcription. Evolved to achieve high rates of Ca²⁺-selective flux, they possess an elaborate mechanism for selection of Ca²⁺ over foreign ions. It has been convincingly linked to competitive binding in the pore, but the fundamental question of how this is reconcilable with high rates of Ca²⁺ transfer remains unanswered. By virtue of their similarity to Ca²⁺, polyvalent cations can interfere with the function of VGCCs and have proven instrumental in probing the mechanisms underlying selective permeation. Recent emergence of crystallographic data on a set of Ca²⁺-selective model channels provides a structural framework for permeation in VGCCs, and warrants a reconsideration of their diverse modulation by polyvalent cations, which can be roughly separated into three general mechanisms: (I) long-range interactions with charged regions on the surface, affecting the local potential sensed by the channel or influencing voltage-sensor movement by repulsive forces (electrostatic effects), (II) short-range interactions with sites in the ion-conducting pathway, leading to physical obstruction of the channel (pore block), and in some cases (III) short-range interactions with extracellular binding sites, leading to non-electrostatic modifications of channel gating (allosteric effects). These effects, together with the underlying molecular modifications, provide valuable insights into the function of VGCCs, and have important physiological and pathophysiological implications. Allosteric suppression of some of the pore-forming Ca_vα₁-subunits (Ca_v2.3, Ca_v3.2) by Zn²⁺ and Cu²⁺ may play a major role for the regulation of excitability by endogenous transition metal ions. The fact that these ions can often traverse VGCCs can contribute to the detrimental intracellular accumulation of metal ions following excessive release of endogenous Cu²⁺ and Zn²⁺ or exposure to non-physiological toxic metal ions.
Ankyrin-B regulates Ca<inf>v</inf>2.1 and Ca<inf>v</inf>2.2 channel expression and targeting
2014, Journal of Biological Chemistry
N-type and P/Q-type calcium channels are documented players in the regulation of synaptic function; however, the mechanisms underlying their expression and cellular targeting are poorly understood. Ankyrin polypeptides are essential for normal integral membrane protein expression in a number of cell types, including neurons, cardiomyocytes, epithelia, secretory cells, and erythrocytes. Ankyrin dysfunction has been linked to defects in integral protein expression, abnormal cellular function, and disease. Here, we demonstrate that ankyrin-B associates with Ca_v2.1 and Ca_v2.2 in cortex, cerebellum, and brain stem. Additionally, using in vitro and in vivo techniques, we demonstrate that ankyrin-B, via its membrane-binding domain, associates with a highly conserved motif in the DII/III loop domain of Ca_v2.1 and Ca_v2.2. Further, we demonstrate that this domain is necessary for proper targeting of Ca_v2.1 and Ca_v2.2 in a heterologous system. Finally, we demonstrate that mutation of a single conserved tyrosine residue in the ankyrin-binding motif of both Ca_v2.1 (Y797E) and Ca_v2.2 (Y788E) results in loss of association with ankyrin-B in vitro and in vivo. Collectively, our findings identify an interaction between ankyrin-B and both Ca_v2.1 and Ca_v2.2 at the amino acid level that is necessary for proper Ca_v2.1 and Ca_v2.2 targeting in vivo.
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Worldwide increase in the prevalence of metabolic syndrome and diabetes mellitus type 2 (DM2) during the past decades has converted them into a global epidemic disease. It is not well understood how these metabolic disorders initiate, but an increase in food consumption associated to low physical activity leads to increase in body weight and obesity. This in turn, elevates circulating lipids and cytokines release by adipose tissue, give the organism a chronic inflammation and potentiate insulin secretion, causing insulin resistance. Depending on genetics and probably other environmental factors, after a long period of hyperactivity, pancreatic beta cells become exhausted and DM2 overcomes.
Pancreatic beta cells are the only source of insulin known in mammals. They are unique because of their ability to sense and transform fuels into a chemical signal, which affects mainly all the cells in the organism. Many other factors affect insulin secretion. We will focus on the alterations of glucose-induced insulin secretion coupling, particularly in ionic channels that have crucial importance in this process.
Different channel types can be affected by metabolic syndrome. The most studied are K_ATP and other potassium channels, calcium, sodium, and TRP channels. Much information comes from rodents that do not express exactly the same proportion and type of channels than humans. However, getting insight of how do they participate in insulin secretion and how to modulate them is important to completely understand beta-cell physiology and pathophysiological reactions to metabolic syndrome and diabetes, in order to stop the epidemic of these metabolic disorders.

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Ca2+ channels: diversity of form and function

Abstract

Trends Neurosci

Trends Neurosci

J Biol Chem

J Biol Chem

J Biol Chem

FEBS Lett

Neuron

FEBS Lett

J Biol Chem

Neuron

Nature

J Biol Chem

Science

Nature

J Neurosci

J Physiol

Neuron

Nature

Classes of Calcium Channels in Vertebrate Cells

Annu Rev Pbysiol

Calcium Channels in Vertebrate Cells

Annu Rev Neurosci

Multiple Calcium Channels and Neuronal Function

Science

Restoration of Excitation-Contraction Coupling and Slow Calcium Current in Dysgenic Muscle by Dihydropyridine Receptor Complementary DNA

Nature

Primary Structure and Functional Expression of the Cardiac Dihydropyridine-Sensitive Calcium Channel

Nature

Induction of Calcium Currents by the Expression of the α1-Subunit of the Dihydropyridine Receptor from Skeletal Muscle

Nature

Rat Brain Expresses a Heterogeneous Family of Calcium Channels

Molecular Diversity of L-Type Calcium Channels

J Biol Chem

Primary Structure of a Calcium Channel that is Highly Expressed in the Rat Cerebellum

Regions of the Skeletal Muscle Dihydropyridine Receptor Critical for Excitation-Contraction Coupling

Nature

Ca²⁺ channels: diversity of form and function