Exploring the function and pharmacotherapeutic potential ­of voltage-gated Ca²⁺channels with gene-knockout models

Loss of Cav1.3 Channels Reveals the Critical Role of L-Type and BK Channel Coupling in Pacemaking Mouse Adrenal Chromaffin Cells

“…There are, however, neurons in which Ca 2ϩ channels also contribute to the pacemaker current (Bean, 2007). Cav1.3 L-type channels (LTCCs) are particularly suitable for pacemaking neurons given their low threshold of activation and slow inactivation time course (Platzer et al, 2000;Koschak et al, 2001;Lipscombe et al, 2004;Striessnig and Koschak, 2008). Cav1.3 channels drive the spontaneous firing of dopaminergic neurons in substantia nigra (SNc) (Chan et al, 2007) and striatal neurons (Olson et al, 2005) and are likely to contribute to the spontaneous action potential (AP) firing of suprachiasmatic nucleus (SCN) and midbrain dopamine neurons (Jackson et al, 2004;Puopolo et al, 2007).…”

Pyrimidine-2,4,6-triones are a new class of voltage-gated L-type Ca2+ channel activators

“…They are predominantly located at postsynaptic somatodendritic locations, are often present in the same neuron 6 and shape shortand long-term adaptations of synaptic function 2,4,6,7 . However, they are functionally distinct and contribute differently to various brain functions, such as emotional and drug-taking behaviours and different types of memory [2][3][4] . Cav1.3 comprises onlyB10% of LTCCs in the brain 8 , but due to its more negative activation voltage range it carries inward current at threshold voltages 9,10 .…”

“…Many physiological processes, including muscle, brain, endocrine and sensory function, depend on proper LTCC activity 2 . Mutant mice and inherited human diseases have provided detailed insight into the physiological and pathophysiological role of these channels 2,4 . LTCCs contain high-affinity drug binding sites for dihydropyridines and other chemical classes of organic Ca 2 þ channel blockers 5 .…”

SUMOylation alters CRMP2 regulation of calcium influx in sensory neurons

“…39 Protein SUMOylation has been reported to modulate neurotransmitter release 36 perhaps via N-type calcium channels that, in turn, are modulated by CRMP2. In summary, SUMO regulation of CRMP2/CaV2.2 signaling may have important implications for chronic pain because CaV2.2 channels are genetically 40,41 and clinically 28,42,43 validated targets for pain management. Future work will also investigate whether SUMOylation of CRMP2 affects its other functions, as well as how it regulates its other interactions.…”