Differential expression of BK channel isoforms and β-subunits in rat neuro-vascular tissues

Abstract

We investigated the expression of splice variants and beta-subunits of the BK channel (big conductance Ca2+-activated K+ channel, Slo1, MaxiK, KCa1.1) in rat cerebral blood vessels, meninges, trigeminal ganglion among other tissues. An alpha-subunit splice variant X1(+24) was found expressed (RT-PCR) in nervous tissue only where also the SS4(+81) variant was dominating with little expression of the short form SS4(0). SS4(+81) was present in some cerebral vessels too. The SS2(+174) variant (STREX) was found in both blood vessels and in nervous tissue. In situ hybridization data supported the finding of SS4(+81) and SS2(+174) in vascular smooth muscle and trigeminal ganglion. beta-subunits beta2 and beta4 showed high expression in brain and trigeminal ganglion and some in cerebral vessels while beta1 showed highest expression in blood vessels. beta3 was found only in testis and possibly brain. A novel splice variant X2(+92) was found, which generates a stop codon in the intracellular C-terminal part of the protein. This variant appears non-functional as a homomer but may modulate the function of other splice-variants when expressed in Xenopus oocytes. In conclusion a great number of splice variant and beta-subunit combinations likely exist, being differentially expressed among nervous and vascular tissues.

Sex differences in the inflammatory mediator-induced sensitization of dural afferents

“…These clinical data raise the intriguing possibility that acute deprivation of estrogens associated with the harvest and dissociation of dural afferents from female rats may contribute to the higher proportion of afferents sensitized by IM from females compared with males. It is also tempting to suggest that such a mechanism contributes to the sex difference in the manifestation of migraine given evidence that gonadal hormones, in particular estrogens, can directly influence the properties [i.e., L-type Ca 2ϩ channels (Mermelstein et al 1996)] and/or expression pattern [i.e., splice variants of the BK Ca 2ϩ -modulated K ϩ channels (Poulsen et al 2009)] of ion channels that influence neuronal excitability. However, increasing awareness of childhood migraine (Bigal and Arruda 2010) and the persistence of migraine in a significant proportion of postmenopausal women (MacGregor 2009) suggests that other mechanisms are also likely to contribute to the sex difference in migraine.…”

DiBAC4(3) hits a “sweet spot” for the activation of arterial large-conductance Ca2+-activated potassium channels independently of the β1-subunit

“…8). Alternatively, some residual brain artery-specific expression of the ␤ 4 -subunit might be present in myocytes from brain arteries (25). We do not have direct molecular evidence to completely rule out this possibility since we have used thoracic aorta for results in Table 1.…”

“…Indeed, Poulsen et al (25) compiled up to 14 alternative splice sites for BK channels. This diversity may, in turn, shape BK channel's pharmacological profile as happens to be the case for the activator Cym04 and the splice variant e9-alt (13).…”

Targeting KCa1.1 Channels with a Scorpion Venom Peptide for the Therapy of Rat Models of Rheumatoid Arthritis

“…In contrast, KCa1.1 α in the CNS is associated with the β4 subunit while the β1 subunit is expressed in smooth muscle cells. Because of the limited tissue distribution of KCa1.1 with the β3 subunit (Mannowetz et al, 2013;Pethő et al, 2016;Poulsen et al, 2009), it may be possible to utilize a blocker that affects KCa1.1 αβ3, but not KCa1.1 αβ4, as a step towards a novel therapy of RA that would not induce side effects in the CNS and as a proof of concept that targeting specific subunits of KCa1.1 can be used for tissuespecific pharmacology.…”

“…JPET Fast Forward. Published on February 16, 2018as DOI: 10.1124 at ASPET Journals on May 7, 2018 jpet.aspetjournals.org Downloaded from JPET #245118 5 subunits of KCa1.1 are found in a variety of tissues including the central nervous system (CNS), smooth muscle, testis, pancreas, and kidney in addition to FLS (Poulsen et al, 2009;Uebele et al, 2000). Paxilline blocks KCa1.1 through allosteric binding to the poreforming α subunit (Sanchez and McManus, 1996) and its systemic administration leads to KCa1.1 block throughout the body, causing detrimental side effects that preclude its use in humans (Imlach et al, 2008;Meredith et al, 2004).…”