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Voltage-Gated Calcium Channels

Voltage-Gated Calcium Channels. Daniel Blackman, Zhihui Zhou, Thomas Arnold. Calcium Ion Channel Family. Cav1 = initiate contraction, secretion, and regulation of gene expression, integration of synaptic input in neurons, and synaptic transmission at ribbon synapses of specialized sensory cells

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Voltage-Gated Calcium Channels

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  1. Voltage-Gated Calcium Channels Daniel Blackman, Zhihui Zhou, Thomas Arnold

  2. Calcium Ion Channel Family • Cav1 = initiate contraction, secretion, and regulation of gene expression, integration of synaptic input in neurons, and synaptic transmission at ribbon synapses of specialized sensory cells • Cav2 = synaptic transmission of fast synapses • Cav3 = important for repetitive or rhythmic firing of Aps (cardiac, thalamic)

  3. Physiology of Voltage-Gated Ca2+ Channels Image taken from Caterall 2011

  4. Image taken from Caterall 2011

  5. Image taken from Caterall 2011

  6. Images taken from Caterall 2011

  7. Images taken from Caterall 2011

  8. Cav1 channel Excitation-contraction coupling Excitation-transcription coupling Excitation-secretion coupling

  9. Excitation-contraction coupling http://www.studyblue.com/notes/note/n/chapter-14-cardiovascular-physiology/deck/9845939

  10. http://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-differen/http://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-differen/

  11. Regulation of excitation-contraction coupling • PKA phosphorylation and its anchoring via a kinase anchoring protein (APAK). • An autoinhibited Ca2+ channel complex with noncovalently bound distal carboxyl-terminus. • Ca2+/ calmodulin-dependent inactivation Image taken from Caterall 2011

  12. Excitation-transcription coupling • Calmodulin binds to the proximal caboxy-terminal domain, the Ca2+ /calmodulin complex moves to the nucleus • The distal carboxy-terminal domain is regulated by Ca2+ in neurons. Image taken from Caterall 2011

  13. Excitation-secretion coupling • Initialization of the secretion of hormones from endocrine cells and release of neurotransmitters. • The distal carboxy-terminal domain plays an autoregulatory role in some Cav 1 channel, such as Cav1.3, Cav1.4.

  14. Cav2 Channels http://physrev.physiology.org/content/90/4/1461

  15. Image taken from Caterall 2011

  16. Cav2 specific information • Initiate fast release of glutamate, GABA, and acetylcholine • SNARE proteins • G Protein subunits are responsible for modulation • Additional binding proteins

  17. Cav3 Channels • Molecular structure: • Negative potential activation (fast inactivation) • Similar to Cav1 and 2 by 25% • Functional • Present in rhythmic structures: • SA node (pacemaker), relay neurons of thalamus (sleep), adrenal cortex (aldosterone) • Mutations can cause absence epilepsy (sleep-like state) • Regulation • Dopamine & NTMs • Angiotensin II

  18. Conlcusion • Ca2+ channel complexes – effector and regulator • Four cases effectors enhance Cav1 & Cav2 • Skeletal muscle • SNARE proteins • Ca2+/CaM-dependent protein kinase II • RIM • Common Theme: “Effector Checkpoint”

  19. Point of interest • LOF for Nav1.7 causes anosmia • Cav2.2 is involved with the first synapse of the olfactory system • Cacna1b LOF mutation causes an absence of Cav2.2 channels • Effects of Lacking Cav2.2 on Olfactory Sensory Neurons (OSN) in the Main Olfactory Bulb (MOB) and on Vomeronasal Sensory Neurons (VSN) in the Accessory Olfactory Bulb (AOB)

  20. Summary • N-type Cav Channels are main contributors to presynaptic release • MOB and AOB respond differently to Cav2.2 mutation • Presence of unknown Cav channel type in MOB • Lack of Cav2.2 does not cause anosmia • Mutation causes hyperaggressive behavior

  21. Question? • Ca2+ and Na+ own nearly identical diameters (2A) • The extracellular concentration of Na+ is 70-fold higher than Ca2+ • The conductance of Na+ is more than 500-fold lower than Ca2+ via Cav channel How the Cav channel keeps the high selectivity of Ca2+ ?

  22. Selectivity filter NavAb: 175TLESWSM181, outward sodium current CavAb: 175TLDDWSD181, inward calcium current

  23. No significant alteration in backbone structure between NavAb and CavAb------the selectivity is mainly determined by the side chains.

  24. Three Ca2+ - binding sites: • Site 1: the carboxyl groups of D178. • Site 2: four carboxylate oxygen atoms from D177 and four backbone carbonyl oxygen atoms from L176. • Site 3: a plane of four carbonyls from T175 • The bound Ca2+ ion is continuously stabilized in a fully hydrated state through the pore.

  25. D178 VS S178: • Site 1 • Over 100-fold change in PCa:PNa. • D178: forms the first hydrated Ca2+ - binding site • S178: blocks the conduction of Ca2+ by directly binding Ca2+and displacing the hydration shell

  26. D177 VS E177: • Site 2 • 5.5-fold change in PCa:PNa. • D177: interacts with Ca2+ • E177: swings away from the selectivity filter

  27. D181 VS N181 VS M181: • Site 1 • 4- to 5-fold change in PCa:PNa. • D181 an N181: constrains the side-chain of the D178 ring by forming a hydrogen bond. • M181: unconstrains the side-chain of the D178 and results in a blocking Ca2+ tightly bound at Site1.

  28. Binding forces: Site 2> Site 1 > Site 3 • Ca2+ can’t occupy adjacent sites simultaneously due to electrostatic repulsive interactions. • High extracellular concentration of Ca2+ and weak binding of Ca2+ to Site 3 generate a unidirectional flux of Ca2+ .

  29. Direct Recording and molecular identity of the calcium channel of primary cilia Daniel Blackman, Zhihui Zhou, Thomas Arnold

  30. Primary Cilia • Specialized compartments • Calcium signaling • Hedgehog pathways • Human retina pigmented epithelium cells tagged with GFP Image taken from DeCaen et al

  31. Image taken from DeCaen et al

  32. Image taken from DeCaen et al

  33. Polycystin proteins (PC/PKD) • Identified in polycystic kidney disease • Form ion channels at high densities in multiple cell types • Two structural classes (PKD1s and PKD2s) • Hypothesis: PKD1L1-PKD2L1 heteromultermerize to form calcium-permeant ciliary channels

  34. Image taken from DeCaen et al

  35. Conclusion • No Ca2+ current with just PKD1L1 (current observed with PKD2L1) • Only with both PKD1L1 and PKD2L1 was current observed matching human

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