Molecular basis of drug interaction with L-type Ca2+ channels.
Different types of voltage-gated Ca2+ channels exist in the plasma membrane of electrically excitable cells. By controlling depolarization-induced Ca2+ entry into cells they serve important physiological functions, such as excitation-contraction coupling, neurotransmitter and hormone secretion, and neuronal plasticity. Their function is fine-tuned by a variety of modulators, such as enzymes and G-proteins. Block of so-called L-type Ca2+ channels by drugs is exploited as a therapeutic principle to treat cardiovascular disorders, such as hypertension. More recently, block of so-called non-L-type Ca2+ channels was found to exert therapeutic effects in the treatment of severe pain and ischemic stroke. As the subunits of different Ca2+ channel types have been cloned, the modulatory sites for enzymes, G-proteins, and drugs can now be determined using molecular engineering and heterologous expression. Here we summarize recent work that has allowed us to determine the sites of action of L-type Ca2+ channel modulators. Together with previous biochemical, electrophysiological, and drug binding data these results provide exciting insight into the molecular pharmacology of this voltage-gated Ca2+ channel family.
Institut für Biochemische Pharmakologie, Innsbruck, Austria.
J
J
Mitterdorfer
M
M
Grabner
R L
RL
Kraus
S
S
Hering
H
H
Prinz
H
H
Glossmann
J
J
Striessnig
D000345:Affinity Labels; D000494:Allosteric Regulation; D000495:Allosteric Site; D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D000959:Antihypertensive Agents / Q000494:pharmacology; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D020746:Calcium Channels, L-Type; D020013:Calcium Signaling / Q000187:drug effects; D015195:Drug Design; D000939:Epitopes / Q000276:immunology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008954:Models, Biological; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
D000345:Affinity Labels; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D000939:Epitopes; D011993:Recombinant Fusion Proteins; D002118:Calcium