Brace yourself, Grey's Anatomy fans.

According to inside sources, there's a major shakeup coming by the end of this season - one that will result in a Seattle Grace couple calling it quits. But this is heavier than usual.

Apparently, it's "one of the longer-term, most-loved couples" that splits up, and it's "going to leave both of them pretty devastated." Doesn't sound good, does it? There's more still.

The backdrop of the breakup involves "a very serious issue "that it certainly seems like the two cannot get past - and does not arise because either of them have met someone new.

Any guesses?

Everybody's going to be glued to Grey's Anatomy message boards after this.

Meanwhile, there's also going to be a new fling in the hospital we love, and it involves one of the newcomers this season, and someone who's been around for a good long while. 

One clue to the hookup: It stinks (and only die-hard fans of a certain other show will get that reference)! If you have any theories on this, we'd welcome them in the comments.

Finally, we hear that the Grey's Anatomy sixth season finale will be "a serious game changer for every single character." Okay, Shonda Rhimes said that, but it's worth repeating.

Sound off below with who you think the breakup - and hookup - involves, and what you think the upcoming season-ending Grey's Anatomy bonanza will entail ...

Steve Marsi is the Managing Editor of TV Fanatic. Follow him on Google+ or email him here.