Voltage gated Ca+ Flashcards
List the subunits that assemble to form a voltage-gated Ca2+ channel
Ca channels an arise by the combination of five subunits
1) alpha 1
2) beta
3) alpha 2 (highly glycosylated) attaches to sigma subunit by a disulphide link which then anchors to alpha 1)
4) sigma
5) gamma (glycoprotein)
List the subtypes and corresponding properties of CaV channels.
1) High-Voltage Activated (HVA) need a large depolarisation (-20mV) and have VARIBLE/NO inactivation (therefore longlasting =L-TYPE)
2) Low-Voltage Activated (LVA) need a more neg potential to open (-60mV) and have a rapid inactivation(therefore brief lasting (transient=T-TYPE))
3) N-TYPE (neuronal) HVA
4) P-TYPE (purkinje) HVA
5) Q-TYPE (granule neurone) HVA
6) R-TYPE (resistant) H/LVA
What is the mechanism by which phosphorylation regulate the Ca2+ current of CaV2? Why is this important?
example of this is the enhancement of Ca2+ current in the heart by catecholamines, which underlies their positive inotropic action
b-adrenergic agonists increase cardiac action potential amplitude, and muscle contractility and rate by either SHIFTING THE GATING or INCREASING THE NUMBER OF CHANNELS.
b-subunit (b2a) considerably enhanced b-adrenergic agonist activation of CaV1.2 (by phosphorylation of serine 478/479)
PKA kinases can phosphorylate beta subunit’s serine in cardiac tissue too and increases calcium current that way.
Describe the clinical importance of Ca2+ channels.
Different drugs act on specific sites to specifically treat defected isoforms (and the associated dsyfunction)
Three major classes of drugs that act on L-type Ca2+ channels are:
1) Dihydropyridines (DHPs) e.g. nifedipine
2) Phenylalkylamines e.g. verapamil
3) Benzothiazepines e.g. diltiazem
USED TO TREAT HYPERTENTION
CARDIA ARRHYTHMIAS
ISCHAEMIC HEART DISEASE
List the channelopathies that may result from inherited mutations in CaV genes
1) Hypokalemic periodic paralysis (specifically in skeletal muscle where reduced calcium current and muscle weakness)
2) Timothy Syndrome: (cardiac defects, immune deficiency, cognitive abnormalities by loss of channel inactivation and so enhanced calcium entry)
3) Night Blindness: (decreased transmitter released from retinal photoreceptor due to loss of L-type calcium channel)
4) Migraine: (transient migraine attacks from mutations of theP/Q channel causing increased channel activity and transmitter release.)
5) Ataxia: Episodic Ataxia (motor dysfunction from deformation of normal channels and so loss of calcium current
6) Epilepsy: mutations in auxiliary subunits and some have mutations that alter P/Q channel function
7) Autism Spectrum Disorder: mutations in T-type result in reduced channel activity
List some functions of Ca2+channels
In General they allow calcium INFLUX into the cell in response to depolarisation.
they control the following:
1) AP generation and conduction
2) sensory processes
3) muscle contraction
4) secretion of transmitters and hormones
5) cell differentiation and gene expression
What regulates the channels?
hormones, transmitters, protein kinases and phosphatases., toxins and drugs.
How are transmitters released?
Calcium influx is the trigger; it must be at a higher level (Na+ and K+ not needed)
ITS IS A CHEMICAL SIGNAL ON THE CALCIUM (rather than electrical)
Describe the basic structure of the channel
4 repeat domains; each domain with 6 transmembrane segments and a loop between segment 5/6
GLUTAMATE in the P REGION determine the SELECTIVELY for ions
List the location of the different channels types.
1) 1.1-4- Ltype- muscle, neurone, endocrine
2) 2.1- P/Q- nerve terminal
3) 2.2 - N- nerve terminal
4) 2.3 - R- Cell bodies, nerve terminals
5) 3.1-3 - T- muscle, neurone.
Describe the gating was demonstrated? What was found?
Single channel (patch-clamp recordings) found that there was many gating opening times (none[0], Normal [1], long[2])
How is the CaV2 family regulated by G-proteins (Gs, Gi, Go, Gq)?
G protein coupling acts to ALL G PROTEINS INHIBIT calcium current which therefore decreases transmission of vesicles.
It does this by mimicking the actions of the binding agonist; ONLY a Gbetagamma dimer is needed.
Give some examples of calcium channels
1) a2 adrenoceptors
2) opioid receptors
3) GABAb
4) Adenosine A1 receptors
How do L-type channel targeting drugs work?
They STOP Ca2+ influx; Bind to SPECIFIC SITES ON segment5/6 (domains 3/4)
However a drug that binds the same site as another drug can have the opposite effect.
dihydropyridines act as allosteric modulators, in that they alter the GATING behaviour of L-type Ca2+ channels
DHP antagonists act to STABILISE mode 0 (no conductance)
BAYK8644 increases Ca2+ current by STABILISING mode 2 (Long lasting conductance)
phenylalkylamines (verapamil) BLOCK from the intracellular side of the membrane; it needs an open channel block (bind to inner end of pore (S6 in domains III & IV)
The benzothiazepines (diltiazem) appear to act EXTRA cellularly by binding to residues in S5 - S6 linker of domain IV
