Logan Steele
Dihydropyridine (DHP) receptors are a type of voltage sensor that plays a crucial role in skeletal muscle function. Located in the transverse tubule membrane, these receptors are involved in excitation-contraction coupling, controlling the release of calcium from the sarcoplasmic reticulum. Mutations in the DHP receptor, specifically in the alpha 1-subunit, have been linked to hypokalaemic periodic paralysis, an autosomal dominant muscle disease. The DHP receptor also interacts with ryanodine receptors (RyR), contributing to muscle contraction. While the influx of Ca2+ through the DHP receptor is not essential for muscle performance, it may play a role in calcium homeostasis and skeletal muscle development.
| Characteristics | Values |
|---|---|
| Full Form | Dihydropyridine |
| Receptor | DHP receptors of the transverse tubule membrane |
| Role | Plays two roles in excitation-contraction coupling in skeletal muscle |
| Function | a) Voltage sensor which undergoes fast transition to control the release of calcium from sarcoplasmic reticulum |
| b) Conducting unit of a slowly activating L-type calcium channel | |
| DHP Receptor Mutations | Alter calcium currents in human hypokalaemic periodic paralysis myotubes |
| DHP Receptor Channels | Regular geometric arrangement of RyR1 and DHPR channels in skeletal muscle |
| DHP Receptor Subunits | Five subunits including α1.1, β1a, α2/δ, β, and γ |
| DHP Receptor Voltage Sensors | Intracellular |
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What You'll Learn
DHP receptors and excitation-contraction coupling
Dihydropyridine (DHP) receptors play a crucial role in excitation-contraction coupling, particularly in skeletal muscle. In skeletal muscle, DHP receptors control both Ca2+ entry (L-type current) and internal Ca2+ release in a voltage-dependent manner. This process involves the activation of ryanodine receptors (RyR) and the release of Ca2+ ions from the sarcoplasmic reticulum (SR), ultimately leading to muscle contraction.
The role of DHP receptors in excitation-contraction coupling has been extensively studied in various organisms, including rabbits, rats, mice, and the ascidian tunicate Ciona intestinalis. In skeletal muscle, the DHP receptor primarily acts as a "voltage sensor," causing depolarization-induced Ca2+ release from the SR. This function has been observed in both vertebrates and invertebrates.
In contrast, in cardiac muscle E–C coupling, the DHP receptor acts predominantly as an L-type Ca2+ channel for Ca2+-induced Ca2+ release from the SR. This mechanism is supported by studies in which contractions were evoked by electrical stimuli and blocked by the DHP derivative nifedipine, even in the absence of external Ca2+.
The DHP receptor subunit γ1 has been a focus of investigation, particularly in mice models. While its elimination caused a mild increase in voltage-activated Ca2+ release, it did not significantly affect contractile activation in fast or slow-twitch muscles. This suggests that the γ1 subunit may not play a crucial role in normal signal transduction leading to SR Ca2+ release. However, further studies are needed to determine its potential modulatory role in skeletal muscle E-C coupling under special conditions.
Additionally, the DHP receptor's role in excitation-contraction coupling is influenced by its interaction with other receptors and channels, such as ryanodine receptors and calcium channels. The structural and functional aspects of these interactions contribute to our understanding of excitation-contraction coupling and muscle performance.
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DHP receptors as voltage sensors
Dihydropyridine (DHP) receptors, or DHPRs, are voltage-dependent calcium channels that play a crucial role in skeletal muscle function. They are located in the transverse tubule membrane or T-tubule membrane of skeletal muscle cells.
DHPRs have a unique dual functionality in excitation-contraction (EC) coupling. Firstly, they act as voltage sensors, undergoing a fast transition in response to changes in membrane potential. This voltage-sensing function is essential for EC coupling. Secondly, they serve as L-type calcium channels, facilitating the influx of calcium ions (Ca2+).
The voltage-sensing capability of DHPRs is fundamental to their role in skeletal muscle contraction. When skeletal muscle cells are stimulated by depolarization, DHPRs undergo a conformational change. This change triggers the release of calcium ions from the sarcoplasmic reticulum (SR) or intracellular stores, which is essential for muscle contraction. The DHPR-mediated calcium release occurs through ryanodine receptor (RYR) channels, which are calcium release channels.
The interaction between DHPRs and RYRs is crucial for muscle contraction. In vertebrates, a novel mechanism of EC coupling evolved, involving a protein-protein interaction between DHPR and a specific type of RYR (RyR1). This interaction allows the voltage-induced conformational change in DHPR to be transmitted to RyR1, resulting in the release of large amounts of calcium ions and subsequent muscle contraction.
Additionally, DHPRs have been implicated in the generation of slow calcium transients, IP3 production, and early gene expression in skeletal muscle cells. This function is unexpected for a voltage-dependent ion channel, as it involves triggering an intracellular signaling cascade independently of ion permeation. The α1 subunit of the DHPR is particularly important in this context, as it is responsible for generating the slow calcium increase and modulating gene expression.
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DHP receptor mutations
Dihydropyridine (DHP) receptor mutations cause hypokalemic periodic paralysis (hypoKPP), a muscle disease that results in periodic, reversible attacks of muscle weakness. Hypokalaemic periodic paralysis is an autosomal dominant disorder, although it can also occur sporadically. It is characterised by episodic weakness associated with low serum potassium.
Analysis of the messenger ribonucleic acid (mRNA) in the myotubes from patients with either mutation indicated transcription from both the normal and mutant genes. In control myotubes, the existence of the slow L-type current and of two rapidly activating and inactivating calcium current components (T-type with a maximum at about -20 mV and 'third type' with a maximum at +10 to +20 mV) was confirmed. In the myotubes from patients with either mutation, the third-type current component was seen more frequently and, on average, with larger amplitude.
In myotubes with the IVS4 mutation (R1239H), the maximum L-type current density was smaller than in control myotubes. The voltage dependence of activation was normal, and hyperpolarizing prepulses to -120 mV for 20 seconds did not increase the reduced current amplitude during test pulses. In myotubes with the IIS4 mutation (R528H), the L-type current-voltage relation, determined at a holding potential of -90 mV, was normal. However, the voltage dependence of inactivation shifted by about 40 mV to more negative potentials.
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DHP-sensitive Ca channels
Dihydropyridine (DHP) receptors are a type of calcium channel found in skeletal muscle cells. They are located in the transverse tubule membrane and play a crucial role in excitation-contraction coupling, which is the process that initiates muscle contraction. DHP receptors have two main functions: they act as voltage sensors and regulate the release of calcium ions from the sarcoplasmic reticulum, and they form the conducting unit of a slowly activating L-type calcium channel.
The voltage-sensing function of DHP receptors is well established. During skeletal muscle excitation-contraction coupling, sarcolemmal depolarization triggers a conformational change in the DHP receptor, which then activates the release of calcium ions from the sarcoplasmic reticulum, leading to muscle contraction. This voltage-sensing role is essential for the excitation-contraction coupling process.
However, the function of DHP receptors as calcium channels is less clear. While they are known to form L-type calcium channels, some studies suggest that the influx of calcium ions through these channels may not be necessary for muscle performance. For example, a study on a mouse model with blocked DHP-mediated calcium influx showed no significant differences in muscle strength or locomotor activity compared to wild-type controls.
Despite this, DHP-sensitive calcium channels are still an important area of research, particularly in understanding opioid tolerance and supersensitivity. Studies in rats have shown that changes in the density of DHP-sensitive calcium channels in the central nervous system are associated with tolerance and hypersensitivity to the antinociceptive effects of opioid receptor agonists. Further research is needed to fully elucidate the role of DHP-sensitive calcium channels in various physiological and pharmacological processes.
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DHPR-mediated Ca2+ influx
Dihydropyridine (DHP) receptors are present in the transverse tubule membrane of skeletal muscles. They play a role in excitation-contraction coupling by functioning as voltage sensors and L-type calcium channels.
The DHPR-mediated Ca2+ influx refers to the process by which calcium ions enter the cytoplasm of skeletal muscle cells through the DHPR. This influx of calcium ions is essential for muscle contraction. During excitation-contraction coupling, skeletal muscle membrane depolarization triggers the opening of DHPR channels, allowing calcium ions to flow into the cell. This influx of calcium ions then triggers the opening of ryanodine receptors (RyR), which release additional calcium ions from the sarcoplasmic reticulum (SR) into the cytoplasm, leading to muscle contraction.
The DHPR-mediated Ca2+ influx is a rapid process, with the calcium channels exhibiting fast gating kinetics. The activation of these channels is believed to be mediated by a six-state cyclical model, involving two voltage-dependent steps and a voltage-independent rate-limiting step. This rapid activation allows for quick excitation-contraction coupling in skeletal muscles.
While the DHPR's role as a voltage sensor in excitation-contraction coupling is well-established, its function as a calcium channel is less clear. Some studies have shown that DHPR-mediated Ca2+ influx may not be necessary for muscle performance. For example, in a knock-in mouse model where DHPR-mediated Ca2+ influx was eliminated, the mice displayed normal SR Ca2+ release, locomotor activity, motor coordination, muscle strength, and susceptibility to fatigue. Similarly, the N617D mutation in the mouse genome has been shown to abolish DHPR Ca2+ influx without altering EC coupling. These findings suggest that the DHPR-mediated Ca2+ influx may be an evolutionary remnant that is not essential for muscle function.
However, other studies have suggested potential roles for the DHPR Ca2+ inward current. For instance, it may contribute to excitation-coupled Ca2+ entry (ECCE) and play a crucial role in Ca2+ homeostasis or skeletal muscle development. It could also be essential for overall muscle health and fibre integrity. Further research is needed to fully understand the significance of DHPR-mediated Ca2+ influx and its potential functions beyond simple muscle contraction.
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Frequently asked questions
DHP stands for dihydropyridine, which is a receptor in skeletal muscle that plays a role in excitation-contraction coupling.
DHP receptors have two main functions: they act as voltage sensors and control the release of calcium from the sarcoplasmic reticulum, and they provide the conducting unit of a slowly activating L-type calcium channel.
DHP receptors interact with RYR (ryanodine) receptors, which release calcium needed for muscle contraction. This interaction can occur in both forward and retrograde directions.
Mutations in the gene encoding the alpha 1-subunit of the skeletal muscle DHP receptor are responsible for familial hypokalaemic periodic paralysis (HypoPP), an autosomal dominant muscle disease.
