This entry represents the alpha-1D subunits of the Voltage-dependent calcium channel, L-type (LVDCC), which allow cells to slowly inactivate voltage-gated Ca2+ influx to weak depolarisations [[cite:PUB00007839]]. This property allows them to participate in important physiological functions, such as tonic neurotransmitter release in cochlear inner hair cells [[cite:PUB00007840]]. In addition, these properties make them ideally suited to contribute to subthreshold Ca2+ signalling, for example in hippocampal pyramidal cells [[cite:PUB00007841]]. Mutations in this channel have been associated with autism spectrum disorders and epilepsy [[cite:PUB00100491]].
","llm":false,"checked":false,"updated":false},{"text":"Ca2+ ions are unique in that they not only carry charge but they are also the most widely used of diffusible second messengers. Voltage-dependent Ca2+ channels (VDCC) are a family of molecules that allow cells to couple electrical activity to intracellular Ca2+ signalling. The opening and closing of these channels by depolarizing stimuli, such as action potentials, allows Ca2+ ions to enter neurons down a steep electrochemical gradient, producing transient intracellular Ca2+ signals. Many of the processes that occur in neurons, including transmitter release, gene transcription and metabolism are controlled by Ca2+ influx occurring simultaneously at different cellular locales. The pore is formed by the alpha-1 subunit which incorporates the conduction pore, the voltage sensor and gating apparatus, and the known sites of channel regulation by second messengers, drugs, and toxins [[cite:PUB00036034]]. The activity of this pore is modulated by four tightly-coupled subunits: an intracellular beta subunit; a transmembrane gamma subunit; and a disulphide-linked complex of alpha-2 and delta subunits, which are proteolytically cleaved from the same gene product. Properties of the protein including gating voltage-dependence, G protein modulation and kinase susceptibility can be influenced by these subunits.
\r\n\r\nVoltage-gated calcium channels are classified as T, L, N, P, Q and R, and are distinguished by their sensitivity to pharmacological blocks, single-channel conductance kinetics, and voltage-dependence. On the basis of their voltage activation properties, the voltage-gated calcium classes can be further divided into two broad groups: the low (T-type) and high (L, N, P, Q and R-type) threshold-activated channels.
","llm":false,"checked":false,"updated":false},{"text":"L-type calcium channels are formed from alpha-1S, alpha-1C, alpha-1D, and alpha-1F subunits. They are widely distributed and are well characterised in the heart, smooth and skeletal muscle, and some neurons. Their primary functions are in both excitation-contraction and excitation-secretion coupling. In skeletal muscle, the L-type calcium channels act as a voltage sensor for excitation-contraction coupling, and in cardiac muscle, they provide a pathway for calcium influx. Mutations affecting L-type channel subunits result in three diseases: (1) muscular dystrophy, which is characterised by a lack of functional skeletal muscle; (2) hypokalaemic periodic paralysis, which is characterised by episodic attacks of skeletal muscle weakness; and (3) malignant hyperthermia, which is the main cause of death due to anaesthesia. 1,4-dihydropyridines act as antagonists of these channels [[cite:PUB00036043], [cite:PUB00071805]].
","llm":false,"checked":false,"updated":false},{"text":"The alpha-1 subunit forms the pore for the import of extracellular calcium ions and, though regulated by the other subunits, is primarily responsible for the pharmacological properties of the channel [[cite:PUB00036040]]. It shares sequence characteristics with all voltage-dependent cation channels, and exploits the same 6-helix bundle structural motif -in both sodium and calcium channels, this motif is repeated 4 times within the sequence to give a 24-helix bundle. Within each of these repeats, 5 of the transmembrane (TM) segments (S1, S2, S3, S5, S6) are hydrophobic, while the other (S4) is positively charged and serves as the voltage-sensor. Several genes encoding alpha-1 subunits have been identified and can be divided into three functionally distinct families based on sequence homology -Cav1, Cav2 and Cav3 [[cite:PUB00036041]]. The Cav1 family forms channels mediating L-type calcium currents, the Cav2 family mediates P/Q-, N-, and R-type calcium currents, while the Cav3 family mediates T-type calcium currents.
","llm":false,"checked":false,"updated":false}],"wikipedia":null,"literature":{"PUB00071805":{"PMID":15336981,"ISBN":null,"volume":"322","issue":"4","year":2004,"title":"L-type Ca2+ channels in Ca2+ channelopathies.","URL":null,"raw_pages":"1341-6","medline_journal":"Biochem Biophys Res Commun","ISO_journal":"Biochem. Biophys. Res. Commun.","authors":["Striessnig J","Hoda JC","Koschak A","Zaghetto F","Mullner C","Sinnegger-Brauns MJ","Wild C","Watschinger K","Trockenbacher A","Pelster G."],"DOI_URL":"http://dx.doi.org/10.1016/j.bbrc.2004.08.039"},"PUB00007839":{"PMID":11285265,"ISBN":null,"volume":"276","issue":"25","year":2001,"title":"alpha 1D (Cav1.3) subunits can form l-type Ca2+ channels activating at negative voltages.","URL":null,"raw_pages":"22100-6","medline_journal":"J Biol Chem","ISO_journal":"J. Biol. Chem.","authors":["Koschak A","Reimer D","Huber I","Grabner M","Glossmann H","Engel J","Striessnig J."],"DOI_URL":"http://dx.doi.org/10.1074/jbc.M101469200"},"PUB00036043":{"PMID":12825828,"ISBN":null,"volume":"23","issue":"3","year":2003,"title":"1,4-Dihydropyridines as calcium channel ligands and privileged structures.","URL":null,"raw_pages":"293-303","medline_journal":"Cell Mol Neurobiol","ISO_journal":"Cell. Mol. Neurobiol.","authors":["Triggle DJ."],"DOI_URL":"http://dx.doi.org/10.1023/A:1023632419813"},"PUB00036040":{"PMID":11031246,"ISBN":null,"volume":"16","issue":null,"year":2000,"title":"Structure and regulation of voltage-gated Ca2+ channels.","URL":null,"raw_pages":"521-55","medline_journal":"Annu Rev Cell Dev Biol","ISO_journal":"Annu. Rev. Cell Dev. Biol.","authors":["Catterall WA."],"DOI_URL":"http://dx.doi.org/10.1146/annurev.cellbio.16.1.521"},"PUB00036041":{"PMID":10774722,"ISBN":null,"volume":"25","issue":"3","year":2000,"title":"Nomenclature of voltage-gated calcium channels.","URL":null,"raw_pages":"533-5","medline_journal":"Neuron","ISO_journal":"Neuron","authors":["Ertel EA","Campbell KP","Harpold MM","Hofmann F","Mori Y","Perez-Reyes E","Schwartz A","Snutch TP","Tanabe T","Birnbaumer L","Tsien RW","Catterall WA."],"DOI_URL":"http://dx.doi.org/10.1016/S0896-6273(00)81057-0"},"PUB00036034":{"PMID":14657414,"ISBN":null,"volume":"55","issue":"4","year":2003,"title":"International Union of Pharmacology. XL. Compendium of voltage-gated ion channels: calcium channels.","URL":null,"raw_pages":"579-81","medline_journal":"Pharmacol Rev","ISO_journal":"Pharmacol. Rev.","authors":["Catterall WA","Striessnig J","Snutch TP","Perez-Reyes E; International Union of Pharmacology."],"DOI_URL":"http://dx.doi.org/10.1124/pr.55.4.8"},"PUB00007841":{"PMID":8930286,"ISBN":null,"volume":"76","issue":"5","year":1996,"title":"Dihydropyridine-sensitive, voltage-gated Ca2+ channels contribute to the resting intracellular Ca2+ concentration of hippocampal CA1 pyramidal neurons.","URL":null,"raw_pages":"3460-70","medline_journal":"J Neurophysiol","ISO_journal":"J. Neurophysiol.","authors":["Magee JC","Avery RB","Christie BR","Johnston D."],"DOI_URL":"http://intl-jn.physiology.org/cgi/content/abstract/76/5/3460"},"PUB00007840":{"PMID":10639174,"ISBN":null,"volume":"97","issue":"2","year":2000,"title":"Kinetics of exocytosis and endocytosis at the cochlear inner hair cell afferent synapse of the mouse.","URL":null,"raw_pages":"883-8","medline_journal":"Proc Natl Acad Sci U S A","ISO_journal":"Proc. Natl. Acad. Sci. U.S.A.","authors":["Moser T","Beutner D."],"DOI_URL":"http://dx.doi.org/10.1073/pnas.97.2.883"},"PUB00100491":{"PMID":28472301,"ISBN":null,"volume":"26","issue":"15","year":2017,"title":"New gain-of-function mutation shows CACNA1D as recurrently mutated gene in autism spectrum disorders and epilepsy.","URL":null,"raw_pages":"2923-2932","medline_journal":"Hum Mol Genet","ISO_journal":"Hum Mol Genet","authors":["Pinggera A","Mackenroth L","Rump A","Schallner J","Beleggia F","Wollnik B","Striessnig J."],"DOI_URL":null}},"set_info":null,"overlaps_with":[{"accession":"IPR027359","name":"Voltage-dependent channel domain superfamily","type":"homologous_superfamily"}],"counters":{"subfamilies":0,"domain_architectures":0,"interactions":0,"matches":6459,"pathways":7,"proteins":1469,"proteomes":478,"sets":0,"structural_models":{"alphafold":57,"bfvd":0},"structures":5,"taxa":1459},"entry_annotations":{},"cross_references":{},"is_llm":false,"is_reviewed_llm":false,"is_updated_llm":false,"representative_structure":null}}