Roscovitine differentially affects CaV2 and Kv channels by binding to the open state

Buraei, Zafir; Schofield, Geoffrey G.; Elmslie, Keith S.

doi:10.1016/j.neuropharm.2006.10.006

Cited by 49 publications

(96 citation statements)

References 47 publications

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“…It has recently become apparent that roscovitine can affect voltage-dependent ion channels at clinically relevant concentrations (10 -50 M) (10 -13). We (14,15) and others (16,17) have shown that (R)-roscovitine differentially affects voltage-dependent calcium channels. (R)-Roscovitine has two effects on Ca V 2 channels (N-type, P/Q-type, and R-type), which are a rapid onset agonist effect and a more slowly developing antagonist effect (14,15).…”

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confidence: 93%

“…We (14,15) and others (16,17) have shown that (R)-roscovitine differentially affects voltage-dependent calcium channels. (R)-Roscovitine has two effects on Ca V 2 channels (N-type, P/Q-type, and R-type), which are a rapid onset agonist effect and a more slowly developing antagonist effect (14,15). The agonist effect results from (R)-roscovitine specifically binding to activated Ca V 2 channels to slow channel closing (14,15), which results in a significant enhancement of action potential induced calcium influx (14).…”

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confidence: 93%

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confidence: 94%

“…The antagonist effect appears to result from (R)-roscovitine preferentially enhancing occupancy of a "resting" inactivated state to inhibit channel activity (18). Interestingly, the racemic variant (S)-roscovitine has been found to exhibit only an antagonist effect on N-channels, which is one result supporting unique binding sites for the agonist versus antagonist effects (14,15,18).L-type channels are also inhibited by (R)-roscovitine, but by a unique mechanism relative to N-channels (19). L-channel inhibition results from slowed activation and enhanced open state voltage-dependent inactivation (VDI), 3 but the resting inactivated state is not affected.…”

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confidence: 98%

“…(R)-Roscovitine has two effects on Ca V 2 channels (N-type, P/Q-type, and R-type), which are a rapid onset agonist effect and a more slowly developing antagonist effect (14,15). The agonist effect results from (R)-roscovitine specifically binding to activated Ca V 2 channels to slow channel closing (14,15), which results in a significant enhancement of action potential induced calcium influx (14). The antagonist effect appears to result from (R)-roscovitine preferentially enhancing occupancy of a "resting" inactivated state to inhibit channel activity (18).…”

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confidence: 99%

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Roscovitine Binds to Novel L-channel (CaV1.2) Sites That Separately Affect Activation and Inactivation

Yarotskyy

Gao

et al. 2010

Journal of Biological Chemistry

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L-type (Ca V 1.2) calcium channel antagonists play an important role in the treatment of cardiovascular disease. (R)-Roscovitine, a trisubstituted purine, has been shown to inhibit L-currents by slowing activation and enhancing inactivation. This study utilized molecular and pharmacological approaches to determine whether these effects result from (R)-roscovitine binding to a single site. Using the S enantiomer, we find that (S)-roscovitine enhances inactivation without affecting activation, which suggests multiple sites. This was further supported in studies using chimeric channels comprised of N-and L-channel domains. Those chimeras containing L-channel domains I and IV showed (R)-roscovitine-induced slowed activation like that of wild type L-channels, whereas chimeric channels containing L-channel domain I responded to (R)-roscovitine with enhanced inactivation. We conclude that (R)-roscovitine binds to distinct sites on L-type channels to slow activation and enhance inactivation. These sites appear to be unique from other calcium channel antagonist sites that reside within domains III and IV and are thus novel sites that could be exploited for future drug development. Trisubstituted purines could become a new class of drugs for the treatment of diseases related to hyperfunction of L-type channels, such as Torsades de Pointes.Cardiac L-type (Ca V 1.2) channels are central to the regulation of a number of physiological processes (1, 2). Activation of these channels in cardiac and smooth muscle generates the calcium influx that triggers calcium release from the sarcoplasmic reticulum (3) to induce contraction. In contrast, inactivation of these channels provides a negative feedback mechanism to limit calcium influx into the cardiac myocyte, which helps protect from excessive calcium influx that can lead to cardiac arrhythmias (3). L-channel antagonists are routinely used to treat cardiovascular diseases, such as hypertension and angina pectoris (4 -8). Therefore, drugs that inhibit L-channel function have high clinical relevance.Roscovitine is a 2,6,9-trisubstituted purine that was originally developed as a selective blocker of cyclin-dependent kinases (9) and is currently undergoing phase II clinical trials as an anticancer drug (10). It has recently become apparent that roscovitine can affect voltage-dependent ion channels at clinically relevant concentrations (10 -50 M) (10 -13). We (14, 15) and others (16,17) have shown that (R)-roscovitine differentially affects voltage-dependent calcium channels. (R)-Roscovitine has two effects on Ca V 2 channels (N-type, P/Q-type, and R-type), which are a rapid onset agonist effect and a more slowly developing antagonist effect (14, 15). The agonist effect results from (R)-roscovitine specifically binding to activated Ca V 2 channels to slow channel closing (14, 15), which results in a significant enhancement of action potential induced calcium influx (14). The antagonist effect appears to result from (R)-roscovitine preferentially enhancing occupancy of a "resting" inac...

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confidence: 93%

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confidence: 93%

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confidence: 94%

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confidence: 98%

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confidence: 99%

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Roscovitine Binds to Novel L-channel (CaV1.2) Sites That Separately Affect Activation and Inactivation

Yarotskyy

Gao

et al. 2010

Journal of Biological Chemistry

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Alternative roles for Cdk5 in learning and synaptic plasticity

Hawasli

Bibb

2007

Biotechnology Journal

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Protein kinases mediate the intracellular signal transduction pathways controlling synaptic plasticity in the central nervous system. While the majority of protein kinases achieve this function via the phosphorylation of synaptic substrates, some kinases may contribute through alternative mechanisms in addition to enzymatic activity. There is growing evidence that protein kinases may often play structural roles in plasticity as well. Cyclin-dependent kinase 5 (Cdk5) has been implicated in learning and synaptic plasticity. Initial scrutiny focused on its enzymatic activity using pharmacological inhibitors and genetic modifications of Cdk5 cofactors. Quite recently Cdk5 has been shown to govern learning and plasticity via regulation of glutamate receptor degradation, a function that may not dependent on phosphorylation of downstream effectors. From these new studies, two roles emerge for Cdk5 in plasticity: one in which it controls structural plasticity via phosphorylation of synaptic substrates, and a second where it regulates functional plasticity via protein-protein interactions.

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